2-thiopyrimidinones

ABSTRACT

Myeloperoxidase inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat, for example, cardiovascular conditions.

This nonprovisional application claims priority from U.S. ProvisionalApplication No. 61/558,605, filed on Nov. 11, 2011.

BACKGROUND OF THE INVENTION

This invention relates to compounds that are myeloperoxidase inhibitors,pharmaceutical compositions containing such inhibitors and the use ofsuch inhibitors to treat for example, cardiovascular conditionsincluding acute coronary syndrome.

Myeloperoxidase (MPO) is a heme-containing enzyme belonging to theperoxidase superfamily. Examples of animal peroxidases arelactoperoxidase, thyroid peroxidase, eosinophile peroxidase andmyeloperoxidase. Myeloperoxidase is present in primary granules ofneutrophils and to a lesser extent in monocytes. It catalyzes thesynthesis of hypochlorous acid from chloride and hydrogen peroxide. Thehypochlorous acid formed is a powerful oxidant that reacts with avariety of cellular substrates including heme proteins, porphyrins,thiols, iron sulfur centers, nucleotides, DNA, unsaturated lipids,amines and amino acids.

In addition, MPO-catalyzed reactions and their products have been foundto exhibit pro-atherogenic biological activity during the development ofatherosclerosis and cardiovascular disease. For example, themyeloperoxidase plasma content is correlated with the appearance ofcardiovascular disorders in patients suffering unstable angina pectoris.Myeloperoxidase has been reported to contribute to the development ofatherosclerosis by the oxidation of lipid and protein in LDL and HDL.

Furthermore, it has been observed that MPO-generated oxidants reduce thebioavailability of nitric oxide, an important vasodilator. Accordingly,high MPO plasma levels are inversely correlated with the success oftherapy to establish reperfusion of occluded arteries. High MPO levelsare also associated with decreased survival from congestive heartfailure. Additionally, it has been shown that MPO plays a role in plaquedestabilization which leads to plaque rupture and myocardial infarction.

Therefore, MPO is thought to play a role in several processes that leadto cardiovascular disease including 1) impaired cholesterol traffickingand progression of the atherosclerotic plaque towards an unstable state,2) destabilization of the atherosclerotic plaque and plaque rupture, 3)consumption of nitric oxide leading to impaired endothelial function andflow, and 4) pathological tissue damage post ischemia contributing toatrial fibrillation and adverse cardiac remodeling with left ventricularhypertrophy leading to congestive heart failure. As such inhibitors ofMPO activity are proposed to offer significant therapeutic benefit inthe prevention and treatment of cardiovascular disease.

Nevertheless, although MPO has been implicated extensively in theetiology and progression of cardiovascular disease, a biologically safeand non-toxic inhibitor of MPO has yet to be developed. Accordingly,there remains a need for pharmaceutical agents that have myeloperoxidaseinhibiting activity and are useful in the treatment, prevention ordiminution of the manifestations of the maladies described herein.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of the Formula I,

or a pharmaceutically acceptable salt or prodrug thereof whereinR¹ is a five to six membered aromatic ring optionally having one tothree heteroatoms selected independently from nitrogen, sulfur andoxygen or a bicyclic ring consisting of two fused partially saturated,fully saturated or fully unsaturated five to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen; andsaid R¹ is optionally mono-, di-, or tri-substituted independently withcyano, halo, hydroxyl, amino, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)alkoxy(C₁-C₄)alkyl, hydroxy(C₂-C₄)alkoxy, carbamoyl(C₁-C₄)alkoxy,amino(C₂-C₄)alkoxy, cyano(C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylamino, aminocarbonyl, mono-N— ordi-N,N(C₁-C₄)alkylaminocarbonyl, (C₁-C₄)alkylthio, aminosulfonyl,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, or mono-N— ordi-N,N(C₁-C₄)alkylaminosulfonyl, wherein any of the (C₁-C₄)alkyl or(C₁-C₄)alkoxy may be optionally mono-, di- or tri-substituted withfluoro; or wherein R¹ is optionally substituted with a five to sixmembered aromatic ring optionally having one to three heteroatomsselected independently from nitrogen, sulfur and oxygen;R² is a fully saturated, partially unsaturated or fully unsaturated oneto fourteen membered straight carbon chain wherein the carbons, otherthan the connecting carbon,

a. may be branched

b. may optionally be replaced with one or two heteroatoms selectedindependently from oxygen, sulfur and nitrogen, wherein said sulfur isoptionally mono- or di-substituted with oxo,

c. may optionally be mono-, di- or tri-substituted independently withhalo,

d. may optionally be mono-substituted with hydroxy, and

e. may optionally be mono-substituted with oxo,

and wherein the carbon chain is optionally mono-substituted with Z;

wherein Z is a partially saturated, fully saturated or fully unsaturatedthree to seven membered ring optionally having one to three heteroatomsselected independently from oxygen, sulfur and nitrogen, or a bicyclicring consisting of two fused partially saturated, fully saturated orfully unsaturated five to six membered rings, taken independently,optionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen;

wherein said Z is optionally mono-, di- or tri-substituted independentlywith halo, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, aminothioxo,amino(C₁-C₆)alkylcarbonyl, hydroxyl, diaminomethylene, carbamoyl or(C₁-C₆)alkoxy and wherein said (C₁-C₆)alkyl or (C₁-C₆)alkoxy substituentis also optionally substituted with one to three halo, and wherein said(C₁-C₆)alkyl or (C₂-C₆)alkoxy substituent is also optionally substitutedwith one to three hydroxy;

with the proviso that R¹ is not phenyl, and R² is not (C₁-C₆)alkyl.

Yet another aspect of this invention is directed to a method fortreating cardiovascular conditions in a mammal (including a human beingeither male or female) by administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of Formula I,a prodrug thereof, or a pharmaceutically acceptable salt of saidcompound or of said prodrug.

Also provided herein are compositions comprising a pharmaceuticallyeffective amount of one or more of the compounds described herein and apharmaceutically acceptable carrier, vehicle, or diluent.

This invention is also directed to pharmaceutical combinationcompositions comprising: a therapeutically effective amount of acomposition comprising

a first compound, said first compound being a Formula I compound, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug;

a second compound, said second compound being an angiotensin convertingenzyme inhibitor, a HMG-CoA reductase inhibitor, a non-steroidalanti-inflammatory agent, a Factor Xa inhibitor or warfarin; and/oroptionally

a pharmaceutical carrier, vehicle, or diluent.

The present invention is directed to a compound of the Formula IA,

or a pharmaceutically acceptable salt or prodrug thereofwhereinR¹ is a five to six membered aromatic ring optionally having one tothree heteroatoms selected independently from nitrogen, sulfur andoxygen or a bicyclic ring consisting of two fused partially saturated,fully saturated or fully unsaturated five to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen; andsaid R¹ is optionally mono-, di-, or tri-substituted independently withcyano, halo, hydroxyl, amino, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)alkoxy(C₁-C₄)alkyl, hydroxy(C₂-C₄)alkoxy, carbamoyl(C₁-C₄)alkoxy,amino(C₂-C₄)alkoxy, cyano(C₁-C₄)alkyl,(C₁-C₄)alkylcarbonyloxy(C₁-C₄)alkyl,amino(C₁-C₄)alkylcarbonyloxy(C₁-C₄)alkyl,(C₁-C₄)alkylcarbonyloxy(C₁-C₄)alkoxy,amino(C₁-C₄)alkylcarbonyloxy(C₁-C₄)alkoxy, mono-N— ordi-N,N—(C₁-C₄)alkylamino, aminocarbonyl, mono-N— ordi-N,N(C₁-C₄)alkylaminocarbonyl, (C₁-C₄)alkylthio, aminosulfonyl,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, or mono-N— ordi-N,N(C₁-C₄)alkylaminosulfonyl, wherein any of the (C₁-C₄)alkyl or(C₁-C₄)alkoxy may be optionally mono-, di- or tri-substituted withfluoro; orwherein R¹ is optionally substituted with a five to six memberedaromatic ring optionally having one to three heteroatoms selectedindependently from nitrogen, sulfur and oxygen;R² is a fully saturated, partially unsaturated or fully unsaturated oneto fourteen membered straight carbon chain wherein the carbons, otherthan the connecting carbon,

a. may be branched

b. may optionally be replaced with one or two heteroatoms selectedindependently from oxygen and sulfur and may optionally be replaced withone to four nitrogens, wherein said sulfur is optionally mono- ordi-substituted with oxo,

c. may optionally be mono-, di- or tri-substituted independently withhalo,

d. may optionally be mono-substituted with hydroxy, and

e. may optionally be mono-substituted with oxo,

and wherein the carbon chain is optionally mono-substituted with Z;

wherein Z is a partially saturated, fully saturated or fully unsaturatedthree to seven membered ring optionally having one to three heteroatomsselected independently from oxygen, sulfur and nitrogen, or a bicyclicring consisting of two fused partially saturated, fully saturated orfully unsaturated five to six membered rings, taken independently,optionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen;

wherein said Z is optionally mono-, di- or tri-substituted independentlywith amino, halo, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, aminothioxo,amino(C₁-C₆)alkylcarbonyl, hydroxyl, diaminomethylene, carbamoyl or(C₁-C₆)alkoxy and wherein said (C₁-C₆)alkyl or (C₁-C₆)alkoxy substituentis also optionally substituted with one to three halo, and wherein said(C₁-C₆)alkyl or (C₂-C₆)alkoxy substituent is also optionally substitutedwith one to three hydroxy; with the proviso that R¹ is not unsubstitutedphenyl, and R² is not unsubstituted(C₁-C₆)alkyl.

This invention is also directed to a method for treating cardiovascularevents and conditions comprising administering to a mammal in need ofsuch treatment a therapeutically effective amount of a compound ofFormula IA or a prodrug thereof or a pharmaceutically acceptable salt ofsaid compound or of said prodrug wherein the cardiovascular condition orevent is heart failure, congestive heart failure, peripheral arterialdisease, pulmonary hypertension, vasculitis, a primary or secondarymyocardial infarction, ischemia, ischemia reperfusion injury, atrialfibrillation or coronary artery bypass graft surgery (CABG).

This invention is also directed to a method for treating a conditioncomprising administering to a mammal in need of such treatment atherapeutically effective amount of a compound of Formula IA or aprodrug thereof or a pharmaceutically acceptable salt of said compoundor of said prodrug wherein the condition is diabetes, renalinsufficiency, dialysis, delayed graft function, transplant organrejection or nephropathy caused by contrasting agents.

Also provided herein are compositions comprising a pharmaceuticallyeffective amount of one or more of the Formula IA compounds describedherein and a pharmaceutically acceptable carrier, vehicle, or diluent.

This invention is also directed to pharmaceutical combinationcompositions comprising: a therapeutically effective amount of acomposition comprising

a first compound, said first compound being a Formula IA compound, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug;

a second compound, said second compound being an angiotensin convertingenzyme inhibitor, a HMG-CoA reductase inhibitor, a non-steroidalanti-inflammatory agent, a Factor Xa inhibitor or warfarin; and/oroptionally

a pharmaceutical carrier, vehicle, or diluent.

All patents and patent applications referred to herein are herebyincorporated by reference.

Other features and advantages of this invention will be apparent fromthis specification and the appendant claims which describe theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a characteristic x-ray powder diffraction pattern showing acrystalline form of Example 1 (Vertical Axis: Intensity (CPS);Horizontal Axis: Two theta (degrees)).

FIG. 2 is a characteristic x-ray powder diffraction pattern showing acrystalline form of Example 2 (Vertical Axis: Intensity (CPS);Horizontal Axis: Two theta (degrees)).

DETAILED DESCRIPTION OF THE INVENTION

A preferred group of compounds, designated the A Group, contains thosecompounds having the Formula I as shown above wherein R¹ is phenyl,naphthyl, furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,quinolinyl, isoquinolinyl, pyrazolyl, imidazolinyl, cyclopentyl,cyclohexyl, pyrrolyl, indolyl, benzo[b]thiophenyl, benzothiazolyl,benzo[b]furanyl or thiophenyl; and wherein said R¹ is mono-, di-, ortri-substituted independently with cyano, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,hydroxy(C₂-C₄)alkoxy, trifluoro(C₁-C₄)alkyl, trifluoro(C₁-C₄)alkoxy orhalo.

A group of compounds which is preferred among the A Group of compoundsdesignated the B Group, contains those compounds wherein R² is a fullysaturated, partially unsaturated or fully unsaturated one to fourteenmembered straight carbon chain wherein the carbons, other than theconnecting carbon,

a. may be branched

b. may optionally be replaced with one or two heteroatoms selectedindependently from oxygen, sulfur and nitrogen, wherein said sulfur isoptionally mono- or di-substituted with oxo,

c. may optionally be mono-, di- or tri-substituted independently withhalo,

d. may optionally be mono-substituted with hydroxy, and

e. may optionally be mono-substituted with oxo; or

R² is furanyl(C₁-C₄)alkyl, triazolyl(C₁-C₄)alkyl, pyridinyl(C₁-C₄)alkyl,pyrizinyl(C₁-C₄)alkyl, pyridazinyl(C₁-C₄)alkyl, pyrimidinyl(C₁-C₄)alkyl,imidazolyl(C₁-C₄)alkyl or pyrrolidinyl(C₁-C₄)alkyl, said R² ringsoptionally mono-, di- or tri-substituted independently with(C₁-C₄)alkyl, (C₁-C₄)alkoxy or halo.

A group of compounds which is preferred among the B Group of compoundsdesignated the C Group, contains those compounds wherein R¹ is phenyl,naphthyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrimidinyl,pyridazinyl, pyrazinyl, imidazolinyl, furanyl, cyclopentyl, cyclohexyl,pyrrolyl, indolyl, benzo[b]thiophenyl, benzothiazolyl, benzo[b]furanylor thiophenyl; wherein said R¹ is mono-, di-, or tri-substitutedindependently with (C₁-C₄)alkyl, (C₁-C₄)alkoxy, hydroxy(C₂-C₄)alkoxy,cyano, trifluoromethyl, trifluoromethoxy or halo; and

R² is (C₁-C₄)alkoxy(C₁-C₄)alkyl, carboxy(C₁-C₄)alkyl, mono- ordi-hydroxy(C₂-C₆)alkyl, amino(C₂-C₄)alkyl,diaminomethyleneamino(C₂-C₄)alkyl, mono-N— ordi-N,N(C₁-C₄)alkylamino(C₂-C₄)alkyl,(C₁-C₄)alkylcarbonyloxy(C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl,carbamoyl(C₁-C₄)alkyl, carbamoylamino(C₂-C₄)alkyl, mono-N— ordi-N,N(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkyl,amino(C₂-C₄)alkylcarbamoyl(C₁-C₄)alkyl,(C₁-C₄)alkylcarbonylamino(C₂-C₄)alkyl,amino(C₁-C₄)alkylcarbonylamino(C₂-C₄)alkyl,(C₁-C₄)alkoxycarbonylamino(C₂-C₄)alkyl,(C₁-C₄)alkylsulfonylamino(C₂-C₄)alkyl,(C₁-C₄)alkylaminosulfonyl(C₁-C₄)alkyl, aminosulfonyl(C₁-C₄)alkyl,amino(C₃-C₄)hydroxyalkyl or (C₁-C₄)alkylthioalkyl(C₁-C₄).

A group of compounds which is preferred among the C Group of compoundsdesignated the D Group, contains those compounds wherein R¹ is phenyland said R¹ is mono-, di-, or tri-substituted independently withhydroxyethoxy, methyl, methoxy, fluoro or chloro; and

R² is diaminomethyleneamino(C₂-C₄)alkyl, carbamoyl(C₁-C₄)alkyl,hydroxy(C₂-C₄)alkyl, amino(C₂-C₄)alkylcarbamoyl(C₁-C₄)alkyl,(C₁-C₄)alkylcarbonylamino(C₂-C₄)alkyl,amino(C₁-C₄)alkylcarbonylamino(C₂-C₄)alkyl, amino(C₃-C₄)hydroxyalkyl oramino(C₂-C₄)alkyl.

A group of compounds which is preferred among the B Group of compoundsdesignated the E Group, contains those compounds wherein R¹ is phenyl,naphthyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrimidinyl,pyridazinyl, pyrazinyl, imidazolinyl, furanyl, cyclopentyl, cyclohexyl,pyrrolyl, indolyl, benzo[b]thiophenyl, benzothiazolyl, benzo[b]furanylor thiophenyl; wherein said R¹ is mono-, di-, or tri-substitutedindependently with (C₁-C₄)alkyl, (C₁-C₄)alkoxy, hydroxy(C₂-C₄)alkoxy,cyano, trifluoromethyl, trifluoromethoxy or halo; and

R² is triazolyl(C₁-C₄)alkyl, pyridinyl(C₁-C₄)alkyl,pyrizinyl(C₁-C₄)alkyl, pyridazinyl(C₁-C₄)alkyl, pyrimidinyl(C₁-C₄)alkyl,imidazolyl(C₁-C₄)alkyl or pyrrolidinyl(C₁-C₄)alkyl, said R² ringsoptionally mono-, di- or tri-substituted independently with(C₁-C₄)alkyl, (C₁-C₄)alkoxy or halo.

A preferred group of compounds, designated the F Group, contains thosecompounds having the Formula I as shown above wherein R¹ is phenyl andsaid R¹ is mono-, di-, tri-substituted independently with hydroxyethoxy,methyl, methoxy, fluoro or chloro.

A preferred group of compounds, designated the G Group, contains thosecompounds having the Formula I as shown above wherein R² ishydroxy(C₂-C₄)alkyl, diaminomethyleneamino(C₂-C₄)alkyl,carbamoyl(C₁-C₄)alkyl, amino(C₃-C₄)hydroxyalkyl,amino(C₂-C₄)alkylcarbamoyl(C₁-C₄)alkyl,(C₁-C₄)alkylcarbonylamino(C₂-C₄)alkyl,amino(C₁-C₄)alkylcarbonylamino(C₂-C₄)alkyl or amino(C₂-C₄)alkyl.

A preferred group of compounds, designated the H Group, contains thosecompounds having the Formula I as shown above wherein R² is (C₁-C₄)alkylmono- or di-substituted independently with amino, carbamoyl, hydroxyl,(C₁-C₄)alkoxy, amino(C₁-C₄)alkylcarbonylamino,amino(C₂-C₄)alkylcarbamoyl, (C₁-C₄)alkylcarbonylamino ordiaminomethyleneamino.

A preferred group of compounds, designated the I Group, contains thosecompounds wherein the compound is

-   6-(2,4-dimethoxyphenyl)-1-(2-hydroxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one,-   1-(2-aminoethyl)-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one;-   2-[6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide;-   2-[6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide;-   1-(2-aminoethyl)-2-thioxo-6-(2,4,5-trimethoxyphenyl)-2,3-dihydropyrimidin-4(1H)-one;-   1-(3-aminopropyl)-6-(2-methoxy-5-methylphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one;-   N-{2-[6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]ethyl}glycinamide;-   2-{3-[6-(2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]propyl}guanidine,-   1-[(2S)-3-amino-2-hydroxypropyl]-6-(5-chloro-2-methoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one;-   1-[(2R)-3-amino-2-hydroxypropyl]-6-(5-chloro-2-methoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one;-   N-(2-aminoethyl)-2-[6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide;    or-   1-(2-aminoethyl)-6-[2-(2-hydroxyethoxy)phenyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one    or a pharmaceutically acceptable salt thereof.

An especially preferred compound is

-   2-(6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide    or a    pharmaceutically acceptable salt thereof.

It is especially preferred that the compound is

Another especially preferred compound is

-   2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide    or a pharmaceutically acceptable salt thereof.    It is especially preferred that the compound is

A group of compounds which is preferred among the C Group of compoundsdesignated the J Group contains those compounds wherein

R¹ is naphthyl, quinolinyl, isoquinolinyl, indolyl, benzo[b]thiophenyl,benzothiazolyl, benzo[b]furanyl or thiophenyl and said R¹ is mono-, di-,or tri-substituted independently with hydroxyethoxy, methyl, methoxy,fluoro or chloro; and

R² is diaminomethyleneamino(C₂-C₄)alkyl, carbamoyl(C₁-C₄)alkyl,hydroxy(C₂-C₄)alkyl, amino(C₂-C₄)alkylcarbamoyl(C₁-C₄)alkyl,(C₁-C₄)alkylcarbonylamino(C₂-C₄)alkyl,amino(C₁-C₄)alkylcarbonylamino(C₂-C₄)alkyl, amino(C₃-C₄)hydroxyalkyl oramino(C₂-C₄)alkyl.

A preferred group of compounds, designated the K Group, contains thosecompounds wherein the compound is

-   2-[6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide,-   2-[6-(2-methoxy-5-methylphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide;-   1-[(2R)-2-aminopropyl]-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one;-   2-[6-(3-methoxy-2-naphthyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide;    or-   2-[6-(1H-indol-4-yl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide    or a pharmaceutically acceptable salt thereof.

A preferred group of compounds, designated the L Group, contains thosecompounds wherein the compound is

-   2-{6-[2-(2-hydroxyethoxy)-5-methoxyphenyl]-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl}acetamide;-   N-(2-aminoethyl)-2-{6-[2-(2-hydroxyethoxy)-4-methoxyphenyl]-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl}acetamide,-   6-[2-(2-hydroxyethoxy)-4-methoxyphenyl]-1-(2-hydroxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one;-   6-[5-fluoro-2-(2-hydroxyethoxy)phenyl]-1-(2-hydroxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one;    or-   2-{6-[2-(2-hydroxyethoxy)-4-methoxyphenyl]-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl}acetamide    or a pharmaceutically acceptable salt thereof.

An especially preferred compound isN-(2-aminoethyl)-2-[6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamideor a pharmaceutically acceptable salt thereof.

It is especially preferred that the compound is

Preferred cardiovascular conditions include heart failure, congestiveheart failure, peripheral arterial disease, pulmonary hypertension orvasculitis.

Other preferred cardiovascular conditions include unstable angina or apatient that has experienced a myocardial infarction.

Pharmaceutically acceptable salts of the compounds of Formula I or IAinclude the acid addition and base salts thereof. Suitable acid additionsalts are formed from acids which form non-toxic salts. Examples includethe acetate, adipate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,saccharate, stearate, succinate, tannate, tartrate, tosylate,trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, calcium, choline,diethylamine, glycine, lysine, magnesium, meglumine, olamine, potassium,sodium, trimethamine and zinc salts. Hemisalts of acids and bases mayalso be formed, for example, hemisulphate and hemicalcium salts. For areview on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol.Such solvent molecules are those commonly used in the pharmaceuticalart, which are known to be innocuous to the recipient, e.g., water,ethanol, and the like. Other solvents may be used as intermediatesolvates in the preparation of more desirable solvates, such asmethanol, methyl t-butyl ether, ethyl acetate, methyl acetate,(S)-propylene glycol, (R)-propylene glycol, 1,4-butyne-diol, and thelike. The term ‘hydrate’ is employed when said solvent is water.Pharmaceutically acceptable solvates include hydrates and other solvateswherein the solvent of crystallization may be isotopically substituted,e.g. D₂O, d₆-acetone, d₆-DMSO. The term “hydrate” refers to the complexwhere the solvent molecule is water. The solvates and/or hydratespreferably exist in crystalline form.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionised, partially ionised, or non-ionised. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975).

The compounds of the invention include compounds of Formula I or IA ashereinbefore defined, polymorphs, and isomers thereof (includingoptical, geometric and tautomeric isomers) as hereinafter defined andisotopically-labelled compounds of Formula I or IA.

The compounds of the present invention may be administered as prodrugs.Thus certain derivatives of compounds of Formula I or IA which may havelittle or no pharmacological activity themselves can, when administeredinto or onto the body, be converted into compounds of Formula I or IAhaving the desired activity, for example, by hydrolytic cleavage. Suchderivatives are referred to as ‘prodrugs’. [Further information on theuse of prodrugs may be found in ‘Pro-drugs as Novel Delivery Systems,Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and‘Bioreversible Carriers in Drug Design’, Pergamon Press, 1987 (ed. E BRoche, American Pharmaceutical Association).]

Prodrugs can, for example, be produced by replacing appropriatefunctionalities present in the compounds of Formula I or IA with certainmoieties known to those skilled in the art as ‘pro-moieties’ asdescribed, for example, in “Design of Prodrugs” by H Bundgaard(Elsevier, 1985).

Some examples of such prodrugs include:

-   (i) where the compound of Formula I or IA contains a carboxylic acid    functionality (—COOH), an ester thereof, for example, replacement of    the hydrogen with (C₁-C₈)alkyl;-   (ii) where the compound of Formula I or IA contains an alcohol    functionality (—OH), an ether thereof, for example, replacement of    the hydrogen with (C₁-C₆)alkanoyloxymethyl; and-   (iii) where the compound of Formula I or IA contains a primary or    secondary amino functionality (—NH₂ or —NHR where R≠H), an amide    thereof, for example, replacement of one or both hydrogens with    (C₁-C₁₀)alkanoyl.

In addition, certain compounds of Formula I or IA may themselves act asprodrugs of other compounds of Formula I or IA.

Compounds of Formula I or IA containing an asymmetric carbon atom canexist as two or more stereoisomers. Where a compound of Formula I or IAcontains an alkenyl or alkenylene group or a cycloalkyl group, geometriccis/trans (or Z/E) isomers are possible. Where the compound contains,for example, a keto or oxime group or an aromatic moiety, tautomericisomerism (‘tautomerism’) can occur. It follows that a single compoundmay exhibit more than one type of isomerism. For example, the followingis illustrative of tautomers of the compounds of Formula I or IA.

Additional example of tautomerism within the scope of the claimedcompounds is the following illustration of guanidine tautomers of thecompounds.

-   -   Example of guanidine tautomers and geometric isomers

Included within the scope of the claimed compounds of the presentinvention are all stereoisomers, geometric isomers and tautomeric formsof the compounds of Formula (I), including compounds exhibiting morethan one type of isomerism, and mixtures of one or more thereof. Alsoincluded are acid addition or base salts wherein the counterion isoptically active, for example, D-lactate or L-lysine, or racemic, forexample, DL-tartrate or DL-arginine.

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of Formula (I) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number usuallyfound in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Certain isotopically-labelled compounds of Formula (I), for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for thispurpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Tomography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labelled compounds of Formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labelled reagents inplace of the non-labelled reagent previously employed. References hereinto “treat”, “treating”, “treatment” and the like include curative,palliative and prophylactic treatment.

As used herein, the expressions “reaction-inert solvent” and “inertsolvent” refer to a solvent or a mixture thereof which does not interactwith starting materials, reagents, intermediates or products in a mannerwhich adversely affects the yield of the desired product.

By “pharmaceutically acceptable” is meant the carrier, vehicle, ordiluent and/or salt must be compatible with the other ingredients of theformulation, and not deleterious to the recipient thereof.

The term “pharmaceutically effective amount”, as used herein, refers toan amount of the compound of Formula I or IA (or a combination agent ora Formula I or IA compound in combination with a combination agent)sufficient to treat, prevent onset of or delay or diminish the symptomsand physiological manifestations of the indications described herein.

The term “room temperature or ambient temperature” means a temperaturebetween 18 to 25° C., “HPLC” refers to high pressure liquidchromatography, “MPLC” refers to medium pressure liquid chromatography,“TLC” refers to thin layer chromatography, “MS” refers to mass spectrumor mass spectroscopy or mass spectrometry, “NMR” refers to nuclearmagnetic resonance spectroscopy, “DCM” refers to dichloromethane, “DMSO”refers to dimethyl sulfoxide, “DME” refers to dimethoxyethane, “EtOAc”refers to ethyl acetate, “MeOH” refers to methanol, “Ph” refers to thephenyl group, “Pr” refers to propyl, “trityl” refers to thetriphenylmethyl group, “ACN” refers to acetonitrile, “DEAD” refers todiethylazodicarboxylate, and “DIAD” refers todiisopropylazodicarboxylate.

It is to be understood that if a carbocyclic or heterocyclic moiety maybe bonded or otherwise attached to a designated substrate throughdiffering ring atoms without denoting a specific point of attachment,then all possible points are intended, whether through a carbon atom or,for example, a trivalent nitrogen atom. For example, the term “pyridyl”means 2-, 3-, or 4-pyridyl, the term “thienyl” means 2-, or 3-thienyl,and so forth. In general the compounds of this invention can be made byprocesses which include processes analogous to those known in thechemical arts, particularly in light of the description containedherein.

As used herein the term mono-N— or di-N,N—(C₁-C_(x))alkyl . . . refersto the (C₁-C_(x))alkyl moiety taken independently when it isdi-N,N—(C₁-C_(x))alkyl . . . (x refers to integers).

By halo is meant chloro, bromo, iodo, or fluoro.

By alkyl is meant straight chain saturated hydrocarbon or branched chainsaturated hydrocarbon. Exemplary of such alkyl groups (assuming thedesignated length encompasses the particular example) are methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl,neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,hexyl, isohexyl, heptyl and octyl.

By alkoxy is meant straight chain saturated alkyl or branched chainsaturated alkyl bonded through an oxy. Exemplary of such alkoxy groups(assuming the designated length encompasses the particular example) aremethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiarybutoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy,isohexoxy, heptoxy and octoxy.

The following paragraphs describe exemplary ring(s) for the generic ringdescriptions contained herein.

Exemplary five to six membered aromatic rings optionally having one tothree heteroatoms selected independently from oxygen, nitrogen andsulfur include phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl,pyridiazinyl, pyrimidinyl and pyrazinyl.

Exemplary six membered rings include 2H-pyranyl, 4H-pyranyl, pyridinyl,piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl,1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl,piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl,6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl,1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl,1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,4,2-oxadiazinyl and1,3,5,2-oxadiazinyl.

Exemplary bicyclic rings consisting of two fused partially saturated,fully saturated or fully unsaturated five or six membered rings, takenindependently, optionally having one to three heteroatoms selectedindependently from nitrogen, sulfur and oxygen include indolizinyl,indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl,cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl,isobenzofuryl, benzo[b]thienyl, benzo[c]thienyl, 1H-indazolyl,indoxazinyl, benzoxazolyl, benzimidazolyl, benzthiazolyl, purinyl,4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl,isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl,pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl,pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl,1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and4H-1,4-benzoxazinyl.

Certain processes for the manufacture of the compounds of this inventionare provided as further features of the invention and are illustrated bythe following reaction schemes. Other processes may be described in theexperimental section. Specific synthetic schemes for preparation of thecompounds of Formula I or IA are outlined below.

As an initial note, in the preparation of the Formula I or IA compoundsit is noted that some of the preparation methods useful for thepreparation of the compounds described herein may require protection ofremote functionality (e.g., primary amine, secondary amine, carboxyl inFormula I or IA precursors). The need for such protection will varydepending on the nature of the remote functionality and the conditionsof the preparation methods. The need for such protection is readilydetermined by one skilled in the art. The use of suchprotection/deprotection methods is also within the skill in the art. Fora general description of protecting groups and their use, see T. W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, NewYork, 1991.

For example, certain compounds contain primary amines or carboxylic acidfunctionalities which may interfere with reactions at other sites of themolecule if left unprotected. Accordingly, such functionalities may beprotected by an appropriate protecting group which may be removed in asubsequent step. Suitable protecting groups for amine and carboxylicacid protection include those protecting groups commonly used in peptidesynthesis (such as N-t-butoxycarbonyl, benzyloxycarbonyl, and9-fluorenylmethylenoxycarbonyl for amines and lower alkyl or benzylesters for carboxylic acids) which are generally not chemically reactiveunder the reaction conditions described and can typically be removedwithout chemically altering other functionality in the Formula I or IAcompound.

Those skilled in the art will recognize that there exists a variety ofmethods for preparing thiouracils, including the condensation of athiourea with various carbonyl containing compounds, or by reaction of auracil with a thiating agent such as phosphorous pentasulfide orLawesson's reagent. In forming the thiouracils of the present inventionit is useful to consider the method of construction in order to enhancethe desired compounds over the variety of possible isomers in aregiospecific manner.

The Formula I or IA thiouracil compounds wherein R¹ and R² are asdescribed above may be prepared from the Formula III enamine by acyclization reaction. The Formula III enamine is cyclized to thecorresponding Formula I or IA thiouracil, for example, by reaction withan isothiocyanate such as benzoyl, carboxyethyl or preferably(trimethylsilyl)isothiocyanate (TMSNCS). The reaction proceeds underreaction conditions such as a polar aprotic solvent (e.g., methyltetrahydrofuran, tetrahydrofuran, dioxane, isobutylnitrile or neat inthe isothiocyanate) at a temperature of about 20° C. to about 150° C.,typically about 85° C. (via microwave or thermal heating), for aboutthree hours to about forty-eight hours.

The Formula III enamine may be conveniently prepared from the Formula VIβ-ketoester by reaction with an appropriate R²—NH₂ amine (wherein R² isas described above or wherein reactive functionality in R², such as aprimary amine, is in a suitably a protected form, such as anO-tert-butyl carbamate). For example, the Formula VI β-ketoester isreacted with the R²—NH₂ amine in the presence of a weak acid such asacetic acid in a polar solvent (e.g., methanol, ethanol, isopropanol,toluene or neat in the amine) at a temperature of about 20° C. to about120° C., for about four hours to about seventy-two hours, typicallyabout 80° C. for about 12 hours.

As described above, the Formula VI β-ketoester may be prepared, forexample, from a Formula X methyl ketone, a Formula XV carboxylic acid, aFormula XX aryl halide or other precursors known to those skilled in theart.

The Formula VI β-ketoester is prepared from the Formula X methyl ketoneby carboalkoxylation. For example, the Formula X methyl ketone isreacted with a dialkylcarbonate, preferably dimethyl carbonate, in thepresence of an alkoxide base such as potassium tert-butoxide, in a polarsolvent such as methyl tert-butyl ether or the corresponding alcohol forthe dialkylcarbonate, at a temperature of about 15° C. to about 100° C.,typically ambient temperature, for about four hours to about forty-eighthours, typically twelve hours.

The Formula VI β-ketoester may also be prepared for example from acarboxylic acid. For example, the Formula VI β-ketoester may be preparedfrom an activated carboxylic acid. The Formula XV acid is convenientlyconverted to a corresponding XVII acyl imidazole by reaction with1,1′-carbonyldiimidazole in a polar solvent, typically tetrahydrofuranat a temperature between 0° C. and 100° C., preferably ambienttemperature, for between 1 hour and twenty-four hours, preferably threehours. A solution of the resulting acyl imidazole XVII in a polaraprotic solvent such as tetrahydrofuran is converted to thecorresponding Formula VI β-ketoester by reaction with a solution of anactivated acetate species, such as the enolate of an acetate ester orpreferably ethyl magnesium malonate in a polar aprotic solvent such astetrahydrofuran, at a temperature between −80° C. and 100° C.,preferably ambient temperature, for between one and fourty-eight hours,preferably twelve hours to prepare the corresponding Formula VIβ-ketoester.

Those skilled in the art will recognize that a variety of other methodscan be used to prepare the β-ketoester from an acid.

Those skilled in the art will recognize that the Formula VI β-ketoestersmay also be prepared from esters of Formula XV carboxylic acids, such asmethyl, ethyl, isopropyl, or tert-butyl, preferably the isopropyl esterof Formula XV carboxylic acid by a condensation reaction with anactivated acetate species, such as the enolate of an acetate ester,preferably the enolate of isopropyl acetate, in a polar aprotic solventsuch as tetrahydrofuran, dioxane, or toluene, preferablytetrahydrofuran, at a temperature between −80° C. and 40° C., preferablyambient temperature, for between one and twenty-four hours, preferablytwelve hours to prepare the corresponding Formula VI β-ketoester.

In addition, those skilled in the art will recognize that there are avariety of methods for converting an aryl halide into a β-ketoesterincluding the following exemplary procedures. A Formula XX aryl halide(e.g., an aryl bromide) is combined via a palladium-mediated couplingwith a Formula XXII β-alkoxyacrylate, such as ethyl 3-ethoxyacrylateemploying a palladium catalyst, typically bis(tri-tert-butyl phosphine)palladium (optionally with lithium chloride), in the presence of anamine such as N,N-di-cyclohexylmethylamine under an inert atmospheresuch as nitrogen at a temperature of about 90° C. to about 140° C.,typically at about 110° C., for about four hours to about forty-eighthours, typically 12 hours. The resulting XXV enolether is converted tothe corresponding Formula VI β-ketoester by treatment with an acid suchas aqueous HCl in a polar solvent (e.g., dichloromethane, methanol,acetic acid) at a temperature of about 15° C. to about 40° C., typicallyat about ambient, for about thirty minutes to about six hours.

Alternatively, the Formula III enamine may be prepared from the FormulaXXX propiolate via the following two-step reaction.

A Formula XXXII alkyne is coupled with a Formula XXXV boronic acidwherein R¹ is as described above, to prepare the Formula XXX propiolatevia a transition metal mediated coupling. For example, the appropriateR¹-boronic acid in a polar aprotic solvent such as dichloromethane isreacted with cesium carbonate, copper iodide, silver (I) oxide andtert-butyl propiolate at a temperature of about 60° C. to about 100° C.,typically about 80° C., for about 30 minutes to about six hours.

The resulting Formula XXX propiolate is transformed to the correspondingFormula III enamine by amination with the appropriate R²—NH₂ amine(wherein R² is as defined above) in the presence of a weak acid such asacetic acid. The reaction proceeds in a polar solvent such as ethanol orisopropanol at a temperature of about 60° C. to about 100° C. typically,about 80° C. for about 24 hours to about 72 hours.

The Formula I or IA thiouracil may also be prepared from a Formula LVI6-halothiouracil as shown in Scheme II.

The thiocarbonyl of a Formula LVI halothiouracil is protected, forexample, by reaction with iodomethane in the presence of a base such asdiisopropylethylamine in a polar solvent (e.g., acetonitrile) at atemperature of about 15° C. to about 40° C., typically ambienttemperature, for about eight hours to about twenty-four hours. Theresulting Formula LVII halide undergoes a transition metal mediatedcoupling with the appropriate R¹-metal species (wherein R¹ is as definedabove) by for example reaction with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) andR¹boronic acid (wherein R¹ is as described above) with 1,4 dioxane andaqueous sodium carbonate. The mixture is heated at a temperature ofabout 90° C. to about 150° C., typically by subjecting to microwaveirradiation at 120° C. for about fifteen minutes to about one hour. Theresulting Formula LVIII compound is deprotected by reaction with anucleophile, typically by reaction with ammonium sulfide in a polarsolvent such as pyridine at a temperature of about 60° C. to about 150°C., typically by microwave irradiation at 75° C. for about fifteenminutes to about one hour to prepare the Formula I or IA thiouracil.

The Formula LVI halothiouracils may be prepared from the correspondingFormula LV thiouracils by for example, a two-stepdeprotonation/lithium-halogen-exchange with iodine. Typically thethiouracil is treated with a base such as lithium diisopropylamide in apolar aprotic solvent such as tetrahydrofuran at a temperature of about−20° C. to about −100° C., typically −78° C. Then the solution isallowed to warm to a temperature of about 0° C. to about −25° C.,typically −10° C. for about fifteen minutes to about one hour to preparethe corresponding lithium intermediate followed by cooling to atemperature of about −60° C. to about −80° C., typically −78° C.whereupon the lithium intermediate is reacted with iodine in anappropriate polar aprotic solvent for about 5 minutes to aboutforty-eight hours, typically eight hours.

The Formula IB and LXI thiouracil compounds (wherein R¹ is describedabove, and while R³ and R⁴ are not specifically denoted above, refer tosubstituents that are generally described above) may be prepared fromthe Formula LX enamines as shown in Scheme III. Formula LXI thiouracils,wherein R is an alkyl group such as methyl, ethyl, isopropyl ortert-butyl, preferentially methyl or ethyl, may be converted into thecorresponding carboxylic acid, wherein R═H, by a variety of methodsknown to those skilled in the art such as acid or base hydrolysis,preferably treatment with 5 equivalents of sodium or lithium hydroxide,in a polar solvent such as water, methanol, ethanol, tetrahydrofuran, ora mixture of such solvents, preferably water and ethanol, at atemperature between 0° C. to about 100° C., preferably ambienttemperature, for a period between one hour and twenty-four hours,preferably four hours. The resulting Formula LXI carboxylic acid may beconverted into the Formula IB amide by use of amide coupling reagentsknown to those skilled in the art, such as propane phosphonic acidanhydride (T3P) or (CDI), preferably propane phosphonic acid anhydride,in the presence of an organic base, such as pyridine, triethylamine,imidazole or diisopropylethylamine, preferably diisopropylethylamine, ina polar solvent, such as N,N′-dimethylformamide, methylene chloride orethyl acetate, preferably methylene chloride, at a temperature between0° C. and solvent reflux, preferably ambient temperature, for a periodbetween 15 minutes and forty-eight hours, preferably eighteen hours.

The Formula LXI thiouracil compounds may be prepared from Formula LXenamines by reaction with an isothiocyanate, such as N-benzoyl-,N-carboxyethyl- or preferably (trimethylsilyl)isothiocyanate (TMSNCS)optionally in the presence of a polar aprotic solvent, such as, methyltetrahydrofuran, tetrahydrofuran, dioxane, isobutylnitrile,n-butylacetate, N,N′-dimethylformamide, preferably neat in theisothiocyanate at a temperature between 20° C. and 150° C., typicallyabout 85° C., heating with a microwave reactor or a conventional heatsource, for between 15 minutes and forty-eight hours, preferably threehours.

The Formula IC, LXXI and LXXII thiouracils may be prepared from theFormula LXX thiouracils as shown in Scheme IV.

The Formula IC (thiouracils (wherein R¹ is described above, and whileR³-R⁹ are not specifically denoted above, refer to substituents that aregenerally described above and wherein at least one of R⁶ through R⁹ isbonded to the corresponding guanidine nitrogen through a carbonylmoiety) may be prepared from Formula LXXII thiouracils, which may existin a variety of tautomeric forms such as these shown, by reaction ofLXXII guanidines with an acylating reagent known to those skilled in theart such as an acyl chloride or alkyl chloroformate in the presence ofan aqueous base such as sodium carbonate or sodium bicarbonate in polaraprotic solvent, such as tetrahydrofuran, at a temperature between 0° C.and solvent reflux, preferably ambient temperature, to provide thecorresponding Formula IC guanidines. Alternatively, reaction of LXXIIthiouracils with a dialkyl carbonate, in the presence of an alkoxidebase such as sodium ethoxide, in a polar solvent such as thecorresponding alcohol for the dialkylcarbonate, at a temperature ofbetween 15° C. to about 100° C., preferably at 50° C., for between fourhours and forty-eight hours, preferably fifteen hours provides thecorresponding Formula IC thiouracils.

The Formula LXXII thiouracils may be prepared from the correspondingFormula LXX thiouracils by reaction with R⁷R⁸NCN-containing guanylatingreagent, such as benzotriazole-R⁷R⁸N-methanimine,imidazole-R⁷R⁸N-methanimine, or pyrazole-R⁷R⁸N-methanimine in a polaraprotic solvent, preferably N,N′-dimethylformamide, in the presence of abase, preferably diisopropylethylamine, at a temperature between 15° C.to 60° C., preferably ambient temperature, for between four toseventy-two hours, preferably eighteen hours. Alternatively, Formula LXXamines may be converted to an activated thiouracil LXXI wherein X is aleaving group, such as benzotriazole, imidazole, pyrrazole, by reactionwith a methanimine reagent, such as1,1-di(1H-benzotriazol-1-yl)methanimine,1,1-di(1H-imidazol-1-yl)methanimine or1,1-di(1H-pyrazol-1yl)methanimine, in the presence of a base, such asdiisopropylamine, in a polar aprotic solvent, such asN,N′-dimethylformamide, at a temperature between 15° C. and 100° C.,preferably ambient temperature, for between four hours and forty-eighthours, preferably eighteen hours. The resulting Formula LXXI activatedthiouracils can then be treated with R⁷R⁸NH in the presence of a base,such as diisopropylethylamine, in a polar aprotic solvent, such asN,N′-dimethylformamide, at a temperature between 20° C. and 120° C.,preferably 60° C., for between one hour and 24 hours, preferably threehours to obtain Formula LXXII guanidine thiouracils.

The starting materials and reagents for the above described Formula I orIA compounds, are also readily available or can be easily synthesized bythose skilled in the art using conventional methods of organicsynthesis. For example, many of the compounds used herein, are relatedto, or are derived from compounds in which there is a large scientificinterest and commercial need, and accordingly many such compounds arecommercially available or are reported in the literature or are easilyprepared from other commonly available substances by methods which arereported in the literature.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallization.

Mixtures of stereoisomers may be separated by conventional techniquesknown to those skilled in the art. [see, for example, “Stereochemistryof Organic Compounds” by E L Eliel (Wiley, New York, 1994).]

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor.

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of Formula (I) contains an acidic or basicmoiety, an acid or base such as tartaric acid or 1-phenylethylamine. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on a resin with an asymmetric stationary phase and witha mobile phase consisting of a hydrocarbon, typically heptane or hexane,containing from 0 to 50% isopropanol, typically from 2 to 20%, and from0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration ofthe eluate affords the enriched mixture.

Pharmaceutically acceptable salts of compounds of Formula I or IA may beprepared by one or more of three exemplary methods:

-   (i) by reacting the compound of Formula I or IA with the desired    acid or base;-   (ii) by removing an acid- or base-labile protecting group from a    suitable precursor of the compound of Formula I or IA or by    ring-opening a suitable cyclic precursor, for example, a lactone or    lactam, using the desired acid or base; or-   (iii) by converting one salt of the compound of Formula I or IA to    another by reaction with an appropriate acid or base or by means of    a suitable ion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionization in theresulting salt may vary from completely ionized to almost non-ionized.

The compounds of this invention may also be used in conjunction withother pharmaceutical agents (e.g., antiatherosclerotic andantithrombotic agents) for the treatment of the disease/conditionsdescribed herein.

Combination Agents

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thata compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect. Thus, the methods of prevention and treatment described hereininclude use of combination agents.

The combination agents are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of the present invention that, when administeredalone or in combination with an additional therapeutic agent to amammal, is effective to treat the desired disease/condition e.g.,cardiovascular condition such as acute coronary syndrome.

Additional therapeutic agents include anti-coagulant or coagulationinhibitory agents, anti-platelet or platelet inhibitory agents, thrombininhibitors, thrombolytic or fibrinolytic agents, anti-arrythmic agents,anti-hypertensive agents, calcium channel blockers (L-type and T-type),cardiac glycosides, diuretics, mineralocorticoid receptor antagonists,NO donating agents such as organonitrates, NO promoting agents such asphosphodiesterase inhibitors, cholesterol/lipid lowering agents andlipid profile therapies, anti-diabetic agents, anti-depressants,anti-inflammatory agents (steroidal and non-steroidal),anti-osteoporosis agents, hormone replacement therapies, oralcontraceptives, anti-obesity agents, anti-anxiety agents,anti-proliferative agents, anti-tumor agents, anti-ulcer andgastroesophageal reflux disease agents, growth hormone and/or growthhormone secretagogues, thyroid mimetics (including thyroid hormonereceptor antagonist), anti-infective agents, anti-viral agents,anti-bacterial agents, and anti-fungal agents.

Agents used in an ICU setting are included, for example, dobutamine,dopamine, dpinephrine, nitroglycerin, nitroprusside etc.

Combination agents useful for treating vasculitis are included, forexample, azathioprine, cyclophosphamide, mycophenolate, mofetil,rituximab etc.

In another embodiment, the present invention provides a combinationwherein the second agent is at least one agent selected from a factor Xainhibitor, an anti-coagulant agent, an anti-platelet agent, a thrombininhibiting agent, a thrombolytic agent, and a fibrinolytic agent.

Exemplary factor Xa inhibitors include apixaban and rivaroxaban.

Examples of suitable anti-coagulants for use in combination with thecompounds of the present invention include heparins (e.g., unfractionedand low molecular weight heparins such as enoxaparin and dalteparin).

In another preferred embodiment the second agent is at least one agentselected from warfarin, unfractionated heparin, low molecular weightheparin, synthetic pentasaccharide, hirudin, argatrobanas, aspirin,ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam,diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel,tirofiban, eptifibatide, abciximab, melagatran, disulfatohirudin, tissueplasminogen activator, modified tissue plasminogen activator,anistreplase, urokinase, and streptokinase.

A preferred second agent is at least one anti-platelet agent. Especiallypreferred anti-platelet agents are aspirin and clopidogrel.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function, for example byinhibiting the aggregation, adhesion or granular secretion of platelets.Agents include, but are not limited to, the various known non-steroidalanti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen,sulindac, indomethacin, mefenamate, droxicam, diclofenac,sulfinpyrazone, piroxicam, and pharmaceutically acceptable salts orprodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA)and COX-2 inhibitors such as CELEBREX or piroxicam are preferred. Othersuitable platelet inhibitory agents include Ilb/IIIa antagonists (e.g.,tirofiban, eptifibatide, and abciximab), thromboxane-A2-2.5 receptorantagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors,PDE-III inhibitors (e.g., Pietal, dipyridamole), and pharmaceuticallyacceptable salts or prodrugs thereof.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, is also intended to include ADP (adenosine diphosphate) receptorantagonists, preferably antagonists of the purinergic receptors P₂Y₁ andP₂Y₁₂, with P₂Y₁₂ being even more preferred. Preferred P₂Y₁₂ receptorantagonists include ticagrelor, prasugrel, ticlopidine and clopidogrel,including pharmaceutically acceptable salts or prodrugs thereof.Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrelare also preferred compounds since they are known to be gentle on thegastro-intestinal tract in use.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the granular secretion of plasminogen activator inhibitor-1and/or serotonin) and/or fibrin formation are disrupted. A number ofthrombin inhibitors are known to one of skill in the art and theseinhibitors are contemplated to be used in combination with the presentcompounds. Such inhibitors include, but are not limited to, boroargininederivatives, boropeptides, heparins, hirudin, argatroban, andmelagatran, including pharmaceutically acceptable salts and prodrugsthereof. Boroarginine derivatives and boropeptides include N-acetyl andpeptide derivatives of boronic acid, such as C-terminalalpha-aminoboronic acid derivatives of lysine, ornithine, arginine,homoarginine and corresponding isothiouronium analogs thereof. The termhirudin, as used herein, includes suitable derivatives or analogs ofhirudin, referred to herein as hirulogs, such as disulfatohirudin. Theterm thrombolytics or fibrinolytic agents (or thrombolytics orfibrinolytics), as used herein, denote agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator (natural orrecombinant) and modified forms thereof, anistreplase, urokinase,streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor VIIainhibitors, PAI-1 inhibitors (i.e., inactivators of tissue plasminogenactivator inhibitors), alpha2-antiplasmin inhibitors, and anisoylatedplasminogen streptokinase activator complex, including pharmaceuticallyacceptable salts or prodrugs thereof. The term anistreplase, as usedherein, refers to anisoylated plasminogen streptokinase activatorcomplex, as described, for example, in EP 028,489, the disclosure ofwhich is hereby incorporated herein by reference herein. The termurokinase, as used herein, is intended to denote both dual and singlechain urokinase, the latter also being referred to herein asprourokinase.

Examples of suitable anti-arrythmic agents include: Class I agents (suchas propafenone); Class II agents (such as metoprolol, atenolol,carvadiol and propranolol); Class III agents (such as sotalol,dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (suchas ditiazem and verapamil); K⁺ channel openers such as I_(Ach)inhibitors, and I_(Kur) inhibitors (e.g., compounds such as thosedisclosed in WO01/40231).

The compounds of the present invention may be used in combination withantihypertensive agents and such antihypertensive activity is readilydetermined by those skilled in the art according to standard assays(e.g., blood pressure measurements). Examples of suitableanti-hypertensive agents include: alpha adrenergic blockers; betaadrenergic blockers; calcium channel blockers (e.g., diltiazem,verapamil, nifedipine and amlodipine); vasodilators (e.g., hydralazine),diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzthiazide, ethacrynic acidtricrynafen, chlorthalidone, torsemide, furosemide, musolimine,bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors;ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril,ceranopril, cilazapril, delapril, pentopril, quinapril, ramipril,lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan,valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan andcompounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265); DualET/All antagonist (e.g., compounds disclosed in WO 00/01389); neutralendopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACEinhibitors) (e.g., gemopatrilat and nitrates). An exemplary antianginalagent is ivabradine.

Examples of suitable calcium channel blockers (L-type or T-type) includediltiazem, verapamil, nifedipine and amlodipine and mybefradil.

Examples of suitable cardiac glycosides include digitalis and ouabain.

In one embodiment, a Formulae I or IA compound may be co-administeredwith one or more diuretics. Examples of suitable diuretics include (a)loop diuretics such as furosemide (such as LASIX™), torsemide (such asDEMADEX™), bemetanide (such as BUMEX™), and ethacrynic acid (such asEDECRIN™); (b) thiazide-type diuretics such as chlorothiazide (such asDIURIL™, ESIDRIX™ or HYDRODIURIL™), hydrochlorothiazide (such asMICROZIDE™ or ORETIC™), benzthiazide, hydroflumethiazide (such asSALURON™), bendroflumethiazide, methychlorthiazide, polythiazide,trichlormethiazide, and indapamide (such as LOZOL™); (c)phthalimidine-type diuretics such as chlorthalidone (such as HYGROTON™),and metolazone (such as ZAROXOLYN™); (d) quinazoline-type diuretics suchas quinethazone; and (e) potassium-sparing diuretics such as triamterene(such as DYRENIUM™), and amiloride (such as MIDAMOR™ or MODURETICT™).

In another embodiment, a compound of Formula I or IA may beco-administered with a loop diuretic. In still another embodiment, theloop diuretic is selected from furosemide and torsemide. In stillanother embodiment, one or more compounds of Formulae I or IA may beco-administered with furosemide. In still another embodiment, one ormore compounds of Formulae I or IA may be co-administered with torsemidewhich may optionally be a controlled or modified release form oftorsemide.

In another embodiment, a compound of Formulae I or IA may beco-administered with a thiazide-type diuretic. In still anotherembodiment, the thiazide-type diuretic is selected from the groupconsisting of chlorothiazide and hydrochlorothiazide. In still anotherembodiment, one or more compounds of Formulae I or IA may beco-administered with chlorothiazide. In still another embodiment, one ormore compounds of Formulae I or IA may be co-administered withhydrochlorothiazide.

In another embodiment, one or more compounds of Formulae I or IA may beco-administered with a phthalimidine-type diuretic. In still anotherembodiment, the phthalimidine-type diuretic is chlorthalidone.

Examples of suitable combination mineralocorticoid receptor antagonistsinclude sprionolactone and eplerenone.

Examples of suitable combination phosphodiesterase inhibitors include:PDE III inhibitors (such as cilostazol); and PDE V inhibitors (such assildenafil).

The compounds of the present invention may be used in combination withcholesterol modulating agents (including cholesterol lowering agents)such as a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoAsynthase inhibitor, an HMG-CoA reductase gene expression inhibitor, anHMG-CoA synthase gene expression inhibitor, an MTP/Apo B secretioninhibitor, a CETP inhibitor, a bile acid absorption inhibitor, acholesterol absorption inhibitor, a cholesterol synthesis inhibitor, asqualene synthetase inhibitor, a squalene epoxidase inhibitor, asqualene cyclase inhibitor, a combined squalene epoxidase/squalenecyclase inhibitor, a fibrate, niacin, an ion-exchange resin, anantioxidant, an ACAT inhibitor or a bile acid sequestrant or an agentsuch as mipomersen.

Examples of suitable cholesterol/lipid lowering agents and lipid profiletherapies include: HMG-CoA reductase inhibitors (e.g., pravastatin,lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a.itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a.rosuvastatin, or atavastatin or visastatin)); squalene synthetaseinhibitors; fibrates; bile acid sequestrants (such as questran); ACATinhibitors; MTP inhibitors; lipooxygenase inhibitors; choesterolabsorption inhibitors; and cholesteryl ester transfer proteininhibitors.

Anti-inflammatory agents also include sPLA2 and IpPLA2 inhibitors (suchas darapladib), 5 LO inhibitors (such as atrelueton) and IL-1 and IL-1rantagonists (such as canakinumab).

Other atherosclerotic agents include agents that modulate the action ofPCSK9.

Cardiovascular complications of type 2 diabetes are associated withdeleterious levels of MPO, accordingly, the compounds of the presentinvention may be used in combination with anti-diabetic agents,particularly type 2 anti-diabetic agents. Examples of suitableanti-diabetic agents include (e.g. insulins, metfomin, DPPIV inhibitors,GLP-1 agonists, analogues and mimetics, SGLT1 and SGLT2 inhibitors)Suitable anti-diabetic agents include an acetyl-CoA carboxylase-(ACC)inhibitor such as those described in WO2009144554, WO2003072197,WO2009144555 and WO2008065508, a diacylglycerol O-acyltransferase 1(DGAT-1) inhibitor, such as those described in WO09016462 orWO2010086820, AZD7687 or LCQ908, diacylglycerol O-acyltransferase 2(DGAT-2) inhibitor, monoacylglycerol O-acyltransferase inhibitors, aphosphodiesterase (PDE)-10 inhibitor, an AMPK activator, a sulfonylurea(e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide,glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone,glisolamide, tolazamide, and tolbutamide), a meglitinide, an α-amylaseinhibitor (e.g., tendamistat, trestatin and AL-3688), an α-glucosidehydrolase inhibitor (e.g., acarbose), an α-glucosidase inhibitor (e.g.,adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q,and salbostatin), a PPARγ agonist (e.g., balaglitazone, ciglitazone,darglitazone, englitazone, isaglitazone, pioglitazone androsiglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW-1536, GW-1929,GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide(e.g., metformin), a glucagon-like peptide 1 (GLP-1) modulator such asan agonist (e.g., exendin-3 and exendin-4), liraglutide, albiglutide,exenatide (Byetta®), albiglutide, lixisenatide, dulaglutide,semaglutide, N,N-9924, TTP-054, a protein tyrosine phosphatase-1B(PTP-1B) inhibitor (e.g., trodusquemine, hyrtiosal extract, andcompounds disclosed by Zhang, S., et al., Drug Discovery Today,12(9/10), 373-381 (2007)), SIRT-1 inhibitor (e.g., resveratrol,GSK2245840 or GSK184072), a dipeptidyl peptidase IV (DPP-IV) inhibitor(e.g., those in WO2005116014, sitagliptin, vildagliptin, alogliptin,dutogliptin, linagliptin and saxagliptin), an insulin secreatagogue, afatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminalkinase (JNK) inhibitor, glucokinase activators (GKa) such as thosedescribed in WO2010103437, WO2010103438, WO2010013161, WO2007122482,TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658or GKM-001, insulin, an insulin mimetic, a glycogen phosphorylaseinhibitor (e.g. GSK1362885), a VPAC2 receptor agonist, SGLT2 inhibitors,such as those described in E. C. Chao et al. Nature Reviews DrugDiscovery 9, 551-559 (July 2010) including dapagliflozin, canagliflozin,empagliflozin, tofogliflozin (CSG452), ASP-1941, THR1474, TS-071,ISIS388626 and LX4211 as well as those in WO2010023594, a glucagonreceptor modulator such as those described in Demong, D. E. et al.Annual Reports in Medicinal Chemistry 2008, 43, 119-137, GPR119modulators, particularly agonists, such as those described inWO2010140092, WO2010128425, WO2010128414, WO2010106457, Jones, R. M. etal. in Medicinal Chemistry 2009, 44, 149-170 (e.g. MBX-2982, GSK1292263,APD597 and PSN821), FGF21 derivatives or analogs such as those describedin Kharitonenkov, A. et al. et al., Current Opinion in InvestigationalDrugs 2009, 10(4)359-364, TGR5 (also termed GPBAR1) receptor modulators,particularly agonists, such as those described in Zhong, M., CurrentTopics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777, GPR40agonists, such as those described in Medina, J. C., Annual Reports inMedicinal Chemistry, 2008, 43, 75-85, including but not limited toTAK-875, GPR120 modulators, particularly agonists, high affinitynicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, suchas GSK1614235. A further representative listing of anti-diabetic agentsthat can be combined with the compounds of the present invention can befound, for example, at page 28, line 35 through page 30, line 19 ofWO2011005611. Preferred anti-diabetic agents are metformin and DPP-IVinhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin,linagliptin and saxagliptin). Other antidiabetic agents could includeinhibitors or modulators of carnitine palmitoyl transferase enzymes,inhibitors of fructose 1,6-diphosphatase, inhibitors of aldosereductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2,inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g. PKCα,PKCβ, PKCγ), inhibitors of fatty acid synthetase, inhibitors of serinepalmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105,Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostainreceptors (e.g. SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulatorsof PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 familyincluding IL1beta, modulators of RXRalpha. In addition suitableanti-diabetic agents include mechanisms listed by Carpino, P. A.,Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51.

Those skilled in the art will recognize that the compounds of thisinvention may also be used in conjunction with other cardiovascular orcerebrovascular treatments including PCI, stenting, drug eluting stents,stem cell therapy and medical devices such as implanted pacemakers,defibrillators, or cardiac resynchronization therapy.

Myeloperoxidase activity has been demonstrated in neuroinflammatoryconditions, accordingly, the compounds of the present invention may beused in combination with neuroinflammatory and neurodegenerative agentsin mammals. Examples of additional neuroinflammatory andneurodegenerative agents include antidepressants, antipsychotics,anti-pain agents, anti-Alzheimer's agents, and anti-anxiety agents.Examples of particular classes of antidepressants that can be used incombination with the compounds of the invention include norepinephrinereuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs),NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOIs),reversible inhibitors of monoamine oxidase (RIMAs), serotonin andnoradrenaline reuptake inhibitors (SNRIs), corticotropin releasingfactor (CRF) antagonists, and atypical antidepressants. Suitablenorepinephrine reuptake inhibitors include tertiary amine tricyclics andsecondary amine tricyclics. Examples of suitable tertiary aminetricyclics and secondary amine tricyclics include amitriptyline,clomipramine, doxepin, imipramine, trimipramine, dothiepin,butriptyline, nortriptyline, protriptyline, amoxapine, desipramine andmaprotiline. Examples of suitable SSRIs include fluoxetine, fluvoxamine,paroxetine, and sertraline. Examples of monoamine oxidase inhibitorsinclude isocarboxazid, phenelzine, and tranylcyclopramine. Examples ofsuitable reversible inhibitors of monoamine oxidase include moclobemide.Examples of suitable SNRIs of use in the present invention includevenlafaxine. Examples of suitable atypical anti-depressants includebupropion, lithium, trazodone and viloxazine. Examples ofanti-Alzheimer's agents include NMDA receptor antagonists such asmemantine; and cholinesterase inhibitors such as donepezil andgalantamine. Examples of suitable classes of anti-anxiety agents thatcan be used in combination with the compounds of the invention includebenzodiazepines and serotonin 1A receptor (5-HT1A) agonists, and CRFantagonists. Suitable benzodiazepines include alprazolam,chlordiazepoxide, clonazepam, chlorazepate, diazepam, lorazepam,oxazepam, and prazepam. Suitable 5-HT1A receptor agonists includebuspirone and ipsapirone. Suitable CRF antagonists include verucerfont.Suitable atypical antipsychotics include paliperidone, ziprasidone,risperidone, aripiprazole, olanzapine, and quetiapine. Suitable nicotineacetylcholine agonists include CP-601927 and varenicline. Anti-painagents include pregabalin, gabapentin, clonidine, neostigmine, baclofen,midazolam, ketamine and ziconotide.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when a Formula I or IA compound and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

In combination therapy treatment, both the compounds of this inventionand the other drug therapies are administered to mammals (e.g., humans,male or female) by conventional methods.

The Formula I or IA compounds of this invention, their prodrugs and thesalts of such compounds and prodrugs are all adapted to therapeutic useas agents that inhibit myeloperoxidase in mammals, particularly humansand thus are useful for the treatment of the various conditions (e.g.,those described herein) in which such action is implicated.

It is believed that myeloperoxidase is involved in the pathologicoxidation of proteins, lipids and nucleic acids and contributes todysfunctional cholesterol metabolism, tissue damage, and organdysfunction and can induce or contribute to the development ofcardiovascular diseases and associated adverse outcomes.

The disease/conditions that can be treated in accordance with thepresent invention include, but are not limited to, cardiovascularconditions, diabetes (e.g., type II) and diabetic complications,vascular conditions, neuroinflammatory conditions, neurodegenerativeconditions, pain, cancer, sepsis, NASH (non-alcoholicsteatatohepatitis), pulmonary injury and hypertension, renal diseases,and vasculitis syndromes especially those related to ANCA(anti-neutrophil cytoplasmic antibodies) and the like.

Given the positive correlation between activation of the myeloperoxidasewith the development of cardiovascular and associateddisease/conditions, Formula I or IA compounds of this invention, theirprodrugs and the salts of such compounds and prodrugs, by virtue oftheir pharmacologic action, are useful for the prevention, arrestmentand/or regression of atherosclerosis and its associated disease states.

It is believed that MPO exhibits pro-atherogenic biological activityduring the evolution of cardiovascular disease. Furthermore, it has beenobserved that MPO-generated oxidants reduce the bioavailability ofnitric oxide, an important vasodilator. Additionally, it has been shownthat MPO plays a role in plaque destabilization by causing theactivation of metalloproteinases, leading to a weakening of the fibrouscap of the plaques and subsequent plaque destabilization and rupture.Given these wide-ranging effects of MPO, MPO has thus been implicated ina wide variety of cardiovascular diseases.

Cardiovascular conditions include, but are not limited to coronary heartdisease, acute coronary syndrome, ischaemic heart disease, first orrecurrent myocardial infarction, secondary myocardial infarction, non-STsegment elevation myocardial infarction, or ST segment elevationmyocardial infarction, ischemic sudden death, transient ischemic attack,peripheral occlusive arterial disease, angina, atherosclerosis,hypertension, heart failure (such as congestive heart failure),diastolic dysfunction (such as left ventricular diastolic dysfunction,diastolic heart failure, and impaired diastolic filling), systolicdysfunction (such as systolic heart failure with reduced ejectionfraction), atrial fibrillation, arrhythmia (ventricular), ischemia,hypertrophic cardiomyopathy, sudden cardiac death, myocardial andvascular fibrosis, impaired arterial compliance, myocardial necroticlesions, vascular damage, left ventricular hypertrophy, decreasedejection fraction, cardiac lesions, vascular wall hypertrophy,endothelial thickening, fibrinoid necrosis of coronary arteries, adverseremodeling, stroke, and the like. Also, included are venous thrombosis,deep vein thrombosis, thrombophlebitis, arterial embolism, coronaryarterial thrombosis, cerebral arterial thrombosis, cerebral embolism,kidney embolism, pulmonary embolism, and thrombosis resulting from (a)prosthetic valves or other implants, (b) indwelling catheters, (c)stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) otherprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis. It is noted that thrombosis includes occlusion(e.g., after a bypass) and reocclusion (e.g., during or afterpercutaneous transluminal coronary angioplasty).

Cardiovascular complications of type 2 diabetes are associated withdeleterious levels of MPO, accordingly, the compounds of the presentinvention may be used to treat diabetes and diabetic complications suchas macrovascular disease, hyperglycemia, metabolic syndrome, impairedglucose tolerance, hyperuricemia, glucosuria, cataracts, diabeticneuropathy, diabetic nephropathy, diabetic retinopathy, obesity,dyslididemia, hypertension, hyperinsulinemia, and insulin resistancesyndrome.

In addition, linkage of myeloperoxidase activity to disease has beendemonstrated in neuroinflammatory and neurodegenerative conditions.Therefore, the compounds of the present invention are particularlyindicated for use in the treatment of neuroinflammatory andneurodegenerative conditions (i.e., disorders or diseases) in mammalsincluding humans such as multiple sclerosis, migraine; epilepsy;Alzheimer's disease; Parkinson's disease; brain injury; stroke;cerebrovascular diseases (including cerebral arteriosclerosis, cerebralamyloid angiopathy, hereditary cerebral hemorrhage, and brainhypoxia-ischemia); cognitive disorders (including amnesia, seniledementia, HIV associated dementia, Alzheimer's associated dementia,Huntington's associated dementia, Lewy body dementia, vascular dementia,drug related dementia, delirium, and mild cognitive impairment); mentaldeficiency (including Down syndrome and fragile X syndrome); sleepdisorders (including hypersomnia, circadian rhythm sleep disorder,insomnia, parasomnia, and sleep deprivation) and psychiatric disorders(such as anxiety (including acute stress disorder, generalized anxietydisorder, social anxiety disorder, panic disorder, post-traumatic stressdisorder and obsessive-compulsive disorder); factitious disorder(including acute hallucinatory mania); impulse control disorders(including compulsive gambling and intermittent explosive disorder);mood disorders (including bipolar I disorder, bipolar II disorder,mania, mixed affective state, major depression, chronic depression,seasonal depression, psychotic depression, and postpartum depression);psychomotor disorder; psychotic disorders (including schizophrenia,schizoaffective disorder, schizophreniform, and delusional disorder);drug dependence (including narcotic dependence, alcoholism, amphetaminedependence, cocaine addiction, nicotine dependence, and drug withdrawalsyndrome); eating disorders (including anorexia, bulimia, binge eatingdisorder, hyperphagia, and pagophagia); and pediatric psychiatricdisorders (including attention deficit disorder, attentiondeficit/hyperactive disorder, conduct disorder, and autism) in a mammal,preferably a human, comprising administering to said mammal atherapeutically effective amount of a compound of Formula I or IA orpharmaceutically acceptable salt thereof.

Other inflammatory diseases or disorders such as asthma, chronicobstructive pulmonary disease, cystic fibrosis, idiopathicpulmonaryfibrosis, acute respiratory distress syndrome, sinusitis,rhinitis, psoriasis, dermatitis, uveitis, gingivitis, atherosclerosis,inflammatory bowel disease, renal glomerular damage, liver fibrosis,sepsis, proctitis, rheumatoid arthritis, and inflammation associatedwith reperfusion injury, spinal cord injury and tissuedamage/scarring/adhesion/rejection.

The term “nephropathy caused by contrasting agents” includes contrastinginduced nephropathy following procedures that utilize imaging agentsincluding cardiac surgery, non-cardiac surgery and transplant surgery.Nephropathy caused by contrasting agents also includes nephropathycaused by the use of enhanced imaging contrasting agents in patientsincluding those at risk of a primary MI or secondary MI.

The utility of the Formula I or IA compounds of the invention, theirprodrugs and the salts of such compounds and prodrugs as medical agentsin the treatment of the above described disease/conditions in mammals(e.g. humans, male or female) is demonstrated by the activity of thecompounds of this invention in conventional in vitro and in vivo assaysdescribed below. The in vivo assays (with appropriate modificationswithin the skill in the art) may be used to determine the activity ofother agents as well as the compounds of this invention. Such assaysalso provide a means whereby the activities of the Formula I or IAcompounds of this invention, their prodrugs and the salts of suchcompounds and prodrugs (or the other agents described herein) can becompared to each other and with the activities of other known compounds.The results of these comparisons are useful for determining dosagelevels in mammals, including humans, for the treatment of such diseases.

The following protocols may of course be varied by those skilled in theart.

MPO Amplex Red Activity Assay.

MPO peroxidase activity was measured by monitoring the formation ofresorufin generated from the oxidation of Amplex Red(10-Acetyl-3,7-dihydroxyphenoxazine) (Invitrogen, Carlsbad, Calif.) byMPO (Gomes, Fernandes et al. 2005). Assay mixtures (100 μL total volume)contained 50 mM NaPi pH 7.4, 150 mM NaCl, 1 mM DTPA(diethylenetriaminepentaacetic acid), 2% DMSO, 2 μM H₂O₂, 30 μM AmplexRed and the reaction was initiated by the addition of 100 μM MPO(purified from human polynuclear leukocytes and purchased fromCalbiochem/EMD Biosciences, Gibbstown, N.J.). All assays were performedin 96-well, half-area, black, nonbinding surface, polystyrene plates(Corning) and the production of resorufin (excitation 530 nm, emission580 nm) was monitored every 20 sec on a Spectramax M2 MicroplateSpectrophotometer (Molecular Devices, Palo Alto, Calif.) equipped withSoftmax Pro software (Molecular Devices, Palo Alto, Calif.). Reactionsto determine the background reaction rate consisted of all assaycomponents and 4 μL of 500 unit/mL bovine catalase (Sigma) in 50 mM KPipH 7.0. The background rate was subtracted from each reaction progresscurve. All data was analyzed using non-linear regression analysis inMicrosoft Excel and Kaleidagraph (Synergy Software).

To determine inhibitor potency (k_(inact)/K_(I)) against MPO, the first600 sec of the reaction progress curves were fit to equation 1, whereV_(o) is the initial rate in RFU/sec and t is time in seconds, to obtainthe first order rate constant for enzyme inactivation (k_(obs)) at eachinhibitor concentration.

$\begin{matrix}{{Product} = {\frac{V_{o}}{k_{obs}}\left\lfloor {1 - {\exp\left( {{- k_{obs}}t} \right)}} \right\rfloor}} & (1)\end{matrix}$Equation 1 is a variation of the standard equation for slow bindinginhibition where the steady state velocity (V_(s)) is set to zero. Eachk_(obs) value was corrected for auto-inactivation of the enzyme bysubtracting the k_(obs) value for the uninhibited reaction. Thecorrected k_(obs) values were then plotted versus inhibitorconcentration ([I]) and fit to equation 2

$\begin{matrix}{k_{obs} = \frac{k_{inact}{I}}{K_{I} + \lbrack I\rbrack}} & (2)\end{matrix}$where k_(inact) is the maximal rate of inactivation and K_(I) is theinhibitor concentration that yields half the rate of maximalinactivation (Copeland 2005).Table 1 and (1A) below provides the myeloperoxidase inhibitory activityfor the Examples below in accordance with the above-described assay.

TABLE 1 MPO k_(inact)/K_(i) for Examples MPO k_(inact)/K_(i) Example #(1/s per M) 1 11600 2 12500 3 29300 4 8790 5 1280 6 12900 7 10900 812100 9 15000 10 619 11 6880 12 5010 13 745 14 5310 15 5420 16 6510 174460 18 8280 19 1960 20 1330 21 4530 22 6340 23 991 24 7640 25 9210 263180 27 15800 28 13700 29 14900 30 5870 31 7680 32 2120 33 4520 34 1310035 4110 36 5980 37 6460 38 5240 39 4520 40 6430 41 5000 42 6070 43 3460044 3440 45 4000 46 1110 47 2340 48 6570 49 2230 50 2610 51 6180 52 33.453 3290 54 7070 55 7740 56 4770 57 13100 58 11700 59 8480 60 3470 613530 62 6930 63 12200 64 22500 65 7940 66 1580 67 7520 68 1160 69 425070 1590 71 3570 72 3580 73 9870 74 14400 75 2040 76 4190 77 6660 78 973079 1580 80 4130 81 24300 82 3390 83 3510 84 6630 85 10700 86 3960 8715400 88 898 89 276 90 11600 91 9360 92 22100 93 5120 94 6930 95 1540096 2200 97 6310 98 1870 99 2920 100 16100 101 4140 102 4200 103 41800104 1210 105 27300 106 10500 107 1280 108 5800 109 914 110 864 111 10300112 14900 113 25900 114 9770 115 4380 116 9920 117 11400 118 5500 11925600 120 9720 121 15800 122 9310 123 3780 124 4610 125 10600 126 18200127 5810 128 7680 129 18700 130 4830 131 14500 132 3840 133 15300 1345350 135 6750 136 1920 137 701 138 4530 139 2890 140 10400 141 10500 1424210 143 8110 144 6010 145 5080 146 8950 147 6500 148 6690 149 9770 1508970 151 3740 152 4770 153 2200 154 1070 155 8090 156 16800 157 7320 1581750 159 11400 160 7540 161 29600 162 8950 163 8090 164 14900 165 1280166 8920 167 20300 168 8890 169 17800 170 4030 171 8590 172 2950 1732910 174 10500 175 459 176 2160 177 5130 178 11100 179 2790 180 6960 1817160 182 8200 183 4830 184 5970 185 9740 186 3930 187 5640 188 2180 1892210 190 4090 191 14100 192 10800 193 458 194 2560 195 5350 196 5640 1975650 198 8460 199 9080 200 4930 201 4350 202 8280 203 3450 204 3900 2054900 206 7690 207 2400 208 3760 209 4360 210 968 211 6090 212 7590 2134690 214 10700 215 1920 216 3260 217 3940 218 14100 219 1970 220 2420221 6230 222 9820 223 3000 224 3280 225 5490 226 6280 227 745 228 615229 5900 230 1740 231 1910 232 4520 233 2510 234 3060 235 2690 236 5740237 2360 238 8740 239 1850 240 7070 241 7060 242 142 243 952 244 8970245 1520 246 246 247 3060 248 3590 249 1050 250 7510 251 68 252 2480 25312700 254 5630 255 3550 256 6520 257 3700 258 1460 259 4000 260 19700261 2280 262 1730 263 4340 264 3620 265 3730 266 604 267 3840 268 6640269 9510 270 20500 271 2010 272 3160 273 8180 274 22800 275 4730 2766710 277 767 278 1560 279 386 280 430 281 1060 282 1180 283 2790 2841470 285 1750 286 1500 287 2130 288 4230 289 1580 290 1890 291 2450 2921070 293 1810 294 1910 295 793 296 1570 297 762 298 1080 299 2060 3002460 301 3330 302 3630 303 5270 304 6290 305 6370 306 6740 307 14400 3085340 309 3160 310 3110 311 2080 312 17100 313 973 314 429 315 1420 3163060 317 7380 318 5240 319 7810 320 2390 321 2480 322 2800 323 10200 32411300 325 1160 326 7480 327 1880 328 4370 329 963 330 5210 331 6330 3323270 333 6100 334 6840 335 9820 336 589 337 13200 338 1280 339 10400 3401450 341 14300 342 817 343 3570 344 8480 345 946 346 5890 347 378 3481400Table 1A below provides the myeloperoxidase inhibitory activity for theExamples below in accordance with the above-described assay.

TABLE 1A MPO k_(inact)/K_(i) for Examples MPO k_(inact)/K_(i) Example #(1/s per M) 349 3630 350 8740 351 7870 352 6720 353 11000 354 1830 3551540 356 2910 357 2940 358 1710 359 2660 360 2280 361 2060 362 2690 3639680 364 6580 365 9290 366 13600 367 1340 368 3270 369 8040 370 9060 3714570 372 6250 373 12800 374 4600 375 11300 376 7870 377 8770 378 5040379 7370 380 4470 381 1970 382 2310 383 5230 384 2930 385 3530 386 4960387 4720 388 8690 389 4910 390 6250 391 3480 392 5830 393 13600 394 4020395 6980 396 10900 397 4050 398 4780 399 4860 400 2650 401 4060 402 4810403 13300 404 6200 405 5970 406 4480 407 18700 408 9890 409 18000 4103150 411 15000 412 3980 413 6560 414 1680 415 3910 416 4480 417 9280 41811500 419 1200 420 5210 421 4950 422 4460 423 3290 424 6870 425 13400426 4410 427 5360 428 5890 429 6620 430 9440 431 3440 432 1410 433 3490434 4070 435 2420 436 3710 437 3400 438 7550 439 9200 440 3310 441 3260442 12300 443 7330 444 17400 445 7350 446 14200 447 17200 448 6490 44912000 450 7730 451 16000 452 11600 453 27800

TPO Amplex Red Activity Assay

TPO activity was measured using the same assay as MPO with 2 μM H₂O₂, 30μM Amplex Red and the reactions were initiated with 1.3 μg of proteinfrom HEK293 cell membranes expressing human TPO. The cDNA encoding 933amino acids of the full length human TPO was cloned into the inducibleexpression vector pcDNA5/frt/to (InVitrogen), stable 293 clones wereselected using 100 ug/ml of hygromycin and 15 ug/ml blasticidine in DMEMw/10% FBS. When cells reached 50-60% confluence, TPO expression wasinduced in medium containing all of above plus 10 ug/ml doxicycline and5 ug/ml hemin (Sigma). Membranes were isolated from HEK293hTPO byharvesting the cells in PBS. The cells were pelleted at 1000×g for 5minutes at 4° C., resuspended in homogenization buffer (1 mM sodiumbicarbonate, pH 7.4) containing EDTA-Free protease inhibitor (Roche),and incubated on ice for 10 minutes followed by Dounce homogenization.Nuclei and unlysed cells were removed by pelleting at 1000×g for 10minutes at 4° C. The supernatant was then centrifuged at 25,000×g for 20minutes at 4° C. The pellet was resuspended in homogenization buffer andcentrifuged again at 25,000×g for 20 minutes at 4° C. The final pelletwas resuspended in storage buffer (50 mM Tris pH 7, 150 mM NaCl)containing protease inhibitors as described above. Membraneconcentration was determined using the BCA Protein Assay (Pierce). TPOactivity was measured using the Amplex Red assay as described above.Aliquots were made based on the activity accordingly and stored at −80°C.

The IC₅₀ values were determined by plotting the initial rates (from thefirst 200 sec of each reaction progress curve) as percentage ofinhibition relative to the uninhibited (DMSO) reaction as a function ofinhibitor concentration. The data were fit to equation 3

$\begin{matrix}{y = \frac{100}{1 + \left( {x/{IC}_{50}} \right)^{s}}} & (3)\end{matrix}$where IC₅₀ is the inhibitor concentration at 50% inhibition and z is theHill slope (the slope of the curve at its inflection point).

REFERENCES

-   Copeland, R. A. (2005). Evaluation of Enzyme Inhibitors in Drug    Discovery A Guide for Medicinal Chemists and Pharmacologists.    Hoboken, Wiley.-   Gomes, A., E. Fernandes, et al. (2005). “Fluorescence probes used    for detection of reactive oxygen species.” J Biochem Biophys Methods    65(2-3): 45-80.

Human Whole Blood Assay for Irreversible Inhibition of MPO

To measure the inhibition of MPO activity in a biological system in thepresent invention, bioassays are performed with human whole blood thatis collected from medication-free, human volunteers in heparin treatedtubes (APP Pharmaceuticals, LLC, cat #NDC#63323-047-10, #4710). Blood isaliquoted and treated with different concentrations of the MPO inhibitoror vehicle control and co-treated with or without bacteriallipopolysaccharide (LPS, InVivogen, cat#tlrl-pelps) to stimulate bloodleukocytes to simultaneously generate H₂0₂ (a required MPO substrate)and the release of MPO. After 4 hour incubation at room temperature theplasma fraction is collected following a 2000×g centrifugation at 4° C.

The plasma fraction is divided into two for analysis of total MPO andactive MPO. The total MPO content is determined using a standardsandwich ELISA (capture and detection antibodies: Cell Sciences,Cat#HP9048, and Cell Sciences, Cat# HM2164, clone 266-6K1) andcalculated relative to a standard curve of purified MPO(myeloperoxidase, Calbiochem, cat#475911) that is prepared by dilutionin the autologous donor plasma. The MPO activity is determined bycapturing the total MPO from plasma using the capture step as describedfor the ELISA method. After washing unbound plasma material includingunreacted MPO inhibitor, MPO reaction substrates are added [H₂0₂ (2 uM)and Amplex Red (Invitrogen, Cat#A12222)] and the Vmax of theMPO-catalyzed conversion of the Amplex Red substrate to resorufin isdetermined by measuring the increase in fluorescence (excitation 530 nM,emission 580 nm) using a fluorescent plate reader in a kinetic analysis.The MPO activity of the captured material is compared to that obtainedwith a standard curve of purified MPO (myeloperoxidase, Calbiochem,cat#475911) that was prepared in autologous donor plasma. The percent of‘active’ myeloperoxidase for each sample is calculated from the ratio ofthe active myeloperoxidase in the Amplex Red assay and the totalmyeloperoxidase from the ELISA for each sample. A dose response curve ofthe MPOi concentration versus MPO activity is then plotted to determinethe IC50 value.

Administration of the compounds of this invention can be via any methodwhich delivers a compound of this invention systemically and/or locally.These methods include oral routes, parenteral, intraduodenal routes,buccal, intranasal etc. Generally, the compounds of this invention areadministered orally, but parenteral administration (e.g., intravenous,intramuscular, subcutaneous or intramedullary) may be utilized, forexample, where oral administration is inappropriate for the target orwhere the patient is unable to ingest the drug.

For administration to human patients, an oral daily dose of thecompounds herein may be in the range 1 mg to 5000 mg depending, ofcourse, on the mode of and frequency of administration, the diseasestate, and the age and condition of the patient, etc. An oral daily doseis in the range of 3 mg to 2000 mg may be used. A further oral dailydose is in the range of 5 mg to 1000 mg. For convenience, the compoundsof the present invention can be administered in a unit dosage form. Ifdesired, multiple doses per day of the unit dosage form can be used toincrease the total daily dose. The unit dosage form, for example, may bea tablet or capsule containing about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175,200, 250, 500, or 1000 mg of the compound of the present invention. Thetotal daily dose may be administered in single or divided doses and may,at the physician's discretion, fall outside of the typical ranges givenherein.

For administration to human patients, an infusion daily dose of thecompounds herein may be in the range 1 mg to 2000 mg depending, ofcourse, on the mode of and frequency of administration, the diseasestate, and the age and condition of the patient, etc. A further infusiondaily dose is in the range of 5 mg to 1000 mg. The total daily dose maybe administered in single or divided doses and may, at the physician'sdiscretion, fall outside of the typical ranges given herein.

These compounds may also be administered to animals other than humans,for example, for the indications detailed above. The precise dosageadministered of each active ingredient will vary depending upon anynumber of factors, including but not limited to, the type of animal andtype of disease state being treated, the age of the animal, and theroute(s) of administration.

A dosage of the combination pharmaceutical agents to be used inconjunction with the Formula I or IA compounds is used that is effectivefor the indication being treated. Such dosages can be determined bystandard assays such as those referenced above and provided herein. Thecombination agents may be administered simultaneously or sequentially inany order.

These dosages are based on an average human subject having a weight ofabout 60 kg to 70 kg. The physician will readily be able to determinedoses for subjects whose weight falls outside this range, such asinfants and the elderly.

Dosage regimens may be adjusted to provide the optimum desired response.For example, a single bolus may be administered, several divided dosesmay be administered over time or the dose may be proportionally reducedor increased as indicated by the exigencies of the therapeuticsituation. It is especially advantageous to formulate parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form, as used herein, refers tophysically discrete units suited as unitary dosages for the mammaliansubjects to be treated; each unit containing a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on (a) the unique characteristics of the chemotherapeuticagent and the particular therapeutic or prophylactic effect to beachieved, and (b) the limitations inherent in the art of compoundingsuch an active compound for the treatment of sensitivity in individuals.

Thus, the skilled artisan would appreciate, based upon the disclosureprovided herein, that the dose and dosing regimen is adjusted inaccordance with methods well-known in the therapeutic arts. That is, themaximum tolerable dose can be readily established, and the effectiveamount providing a detectable therapeutic benefit to a patient may alsobe determined, as can the temporal requirements for administering eachagent to provide a detectable therapeutic benefit to the patient.Accordingly, while certain dose and administration regimens areexemplified herein, these examples in no way limit the dose andadministration regimen that may be provided to a patient in practicingthe present invention.

It is to be noted that dosage values may vary with the type and severityof the condition to be alleviated, and may include single or multipledoses. It is to be further understood that for any particular subject,specific dosage regimens should be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat dosage ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed composition. Forexample, doses may be adjusted based on pharmacokinetic orpharmacodynamic parameters, which may include clinical effects such astoxic effects and/or laboratory values. Thus, the present inventionencompasses intra-patient dose-escalation as determined by the skilledartisan. Determining appropriate dosages and regiments foradministration of the chemotherapeutic agent are well-known in therelevant art and would be understood to be encompassed by the skilledartisan once provided the teachings disclosed herein.

The present invention further comprises use of a compound of Formula Ior IA for use as a medicament (such as a unit dosage tablet or unitdosage capsule). In another embodiment, the present invention comprisesthe use of a compound of Formula I or IA for the manufacture of amedicament (such as a unit dosage tablet or unit dosage capsule) totreat one or more of the conditions previously identified in the abovesections discussing methods of treatment.

A pharmaceutical composition of the invention may be prepared, packaged,or sold in bulk, as a single unit dose, or as a plurality of single unitdoses. As used herein, a “unit dose” is discrete amount of thepharmaceutical composition comprising a predetermined amount of theactive ingredient. The amount of the active ingredient is generallyequal to the dosage of the active ingredient which would be administeredto a subject or a convenient fraction of such a dosage such as, forexample, one-half or one-third of such a dosage.

The compounds described herein may be administered as a formulationcomprising a pharmaceutically effective amount of a compound of FormulaI or IA, in association with one or more pharmaceutically acceptableexcipients including carriers, vehicles and diluents. The term“excipient” herein means any substance, not itself a therapeutic agent,used as a diluent, adjuvant, or vehicle for delivery of a therapeuticagent to a subject or added to a pharmaceutical composition to improveits handling or storage properties or to permit or facilitate formationof a solid dosage form such as a tablet, capsule, or a solution orsuspension suitable for oral, parenteral, intradermal, subcutaneous, ortopical application. Excipients can include, by way of illustration andnot limitation, diluents, disintegrants, binding agents, adhesives,wetting agents, polymers, lubricants, glidants, stabilizers, substancesadded to mask or counteract a disagreeable taste or odor, flavors, dyes,fragrances, and substances added to improve appearance of thecomposition. Acceptable excipients include (but are not limited to)stearic acid, magnesium stearate, magnesium oxide, sodium and calciumsalts of phosphoric and sulfuric acids, magnesium carbonate, talc,gelatin, acacia gum, sodium alginate, pectin, dextrin, mannitol,sorbitol, lactose, sucrose, starches, gelatin, cellulosic materials,such as cellulose esters of alkanoic acids and cellulose alkyl esters,low melting wax, cocoa butter or powder, polymers such aspolyvinyl-pyrrolidone, polyvinyl alcohol, and polyethylene glycols, andother pharmaceutically acceptable materials. Examples of excipients andtheir use may be found in Remington's Pharmaceutical Sciences, 20thEdition (Lippincott Williams & Wilkins, 2000). The choice of excipientwill to a large extent depend on factors such as the particular mode ofadministration, the effect of the excipient on solubility and stability,and the nature of the dosage form.

The compounds herein may be formulated for oral, buccal, intranasal,parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectaladministration or in a form suitable for administration by inhalation.The compounds of the invention may also be formulated for sustaineddelivery.

Methods of preparing various pharmaceutical compositions with a certainamount of active ingredient are known, or will be apparent in light ofthis disclosure, to those skilled in this art. For examples of methodsof preparing pharmaceutical compositions see Remington's PharmaceuticalSciences, 20th Edition (Lippincott Williams & Wilkins, 2000).

Pharmaceutical compositions according to the invention may contain0.1%-95% of the compound(s) of this invention, preferably 1%-70%. In anyevent, the composition to be administered will contain a quantity of acompound(s) according to the invention in an amount effective to treatthe disease/condition of the subject being treated.

Since the present invention has an aspect that relates to the treatmentof the disease/conditions described herein with a combination of activeingredients which may be administered separately, the invention alsorelates to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: a compoundof Formula I or IA a prodrug thereof or a salt of such compound orprodrug and a second compound as described above. The kit comprises ameans for containing the separate compositions such as a container, adivided bottle or a divided foil packet. Typically the kit comprisesdirections for the administration of the separate components. The kitform is particularly advantageous when the separate components arepreferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, etc. . . . Second Week, Monday, Tuesday, . . . ” etc. Othervariations of memory aids will be readily apparent. A “daily dose” canbe a single tablet or capsule or several pills or capsules to be takenon a given day. Also, a daily dose of Formula I or IA compound canconsist of one tablet or capsule while a daily dose of the secondcompound can consist of several tablets or capsules and vice versa. Thememory aid should reflect this.

In another specific embodiment of the invention, a dispenser designed todispense the daily doses one at a time in the order of their intendeduse is provided. Preferably, the dispenser is equipped with amemory-aid, so as to further facilitate compliance with the regimen. Anexample of such a memory-aid is a mechanical counter which indicates thenumber of daily doses that has been dispensed. Another example of such amemory-aid is a battery-powered micro-chip memory coupled with a liquidcrystal readout, or audible reminder signal which, for example, readsout the date that the last daily dose has been taken and/or reminds onewhen the next dose is to be taken.

Also, as the present invention has an aspect that relates to thetreatment of the disease/conditions described herein with a combinationof active ingredients which may be administered jointly, the inventionalso relates to combining separate pharmaceutical compositions in asingle dosage form, such as (but not limited to) a single tablet orcapsule, a bilayer or multilayer tablet or capsule, or through the useof segregated components or compartments within a tablet or capsule.

The active ingredient may be delivered as a solution in an aqueous ornon-aqueous vehicle, with or without additional solvents, co-solvents,excipients, or complexation agents selected from pharmaceuticallyacceptable diluents, excipients, vehicles, or carriers.

An exemplary intravenous formulation is prepared as follows:

Formulation: Intravenous Solution

Ingredient Quantity Active ingredient dissolved in 5% Dextrose 150 mgInjection, USP 5% Dextrose Injection, USP 1.0 mLThe solution of the above ingredients is intravenously administered to apatient at a rate of about 1 mL per minute.

The active ingredient may be formulated as a solid dispersion or as aself emulsified drug delivery system (SEDDS) with pharmaceuticallyacceptable excipients.

The active ingredient may be formulated as an immediate release ormodified release tablet or capsule. Alternatively, the active ingredientmay be delivered as the active ingredient alone within a capsule shell,without additional excipients.

General Experimental Procedures

All chemicals, reagents and solvents were purchased from commercialsources when available and used without further purification. Protonnuclear magnetic spectroscopy (¹H NMR) was recorded with 400 and 500 MHzVarian spectrometers. Chemical shifts are expressed in parts per milliondownfield from tetramethylsilane. The peak shapes are denoted asfollows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;br s, broad singlet. Mass spectrometry (MS) was performed viaatmospheric pressure chemical ionization (APCI) or electron scatter (ES)ionization sources. Observed mass (Obs Mass) reported in the Tablescorrespond to the exact mass of the parent molecule plus one, unlessotherwise noted. Silica gel chromatography was performed primarily usinga medium pressure Biotage or ISCO systems using columns pre-packaged byvarious commercial vendors including Biotage and ISCO. Microanalyseswere performed by Quantitative Technologies Inc. and were within 0.4% ofthe calculated values. The terms “concentrated” and “evaporated” referto the removal of solvent at reduced pressure on a rotary evaporatorwith a bath temperature less than 60° C. The abbreviation “min” and “h”stand for “minutes” and “hours” respectively.

Powder X-Ray Diffraction

Powder diffraction analysis was conducted using a Bruker D8diffractometer equipped with a Cu radiation source, fixed slits(divergence=1.0 mm, anti-scatter=0.6 mm, and receiving=0.6 mm) and ascintillation counter detector. Data was collected in the Theta-Thetagoniometer at the Cu wavelength Kα₁=1.54056 Å from 3.0 to 40.0 degrees2-Theta using a step size of 0.040 degrees and a step time of 2.0second. X-ray tube voltage and amperage were set at 40 kV and 40 mArespectively. Samples were prepared by placement in a Nickel Disk(Gasser & Sons, Inc. Commack, N.Y.) and rotated during data collection.Data were collected and analyzed using Bruker DIFFRAC Plus software(Version 2.6).

I. Beta Keto Ester Route Section A. Carboxylic Acid Route SectionPreparation 1

Ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate

A 3000 mL 3-necked round-bottomed flask flushed with nitrogen wascharged with magnesium ethoxide (67.46 g, 589.51 mmoles) and THF (1100mL), and the resulting mixture was stirred as ethyl hydrogen malonate(162.26 g, 1.18 moles; 145.00 mL diluted in 100 ml of THF) was added andthe mixture was heated at 45° C. for 4 hours. Meanwhile, a 2000 mL3-necked round-bottomed flask flushed with nitrogen was charged with5-chloro-2-methoxybenzoic acid (100 g, 536 mmoles) and THF (600 mL). Tothis mixture stirring at room temperature was added1,1′-carbonyldiimidazole (95.59 g, 589.5 mmoles) in portions to avoidexcess foaming. After stirring for 3 hours at room temperature thesecond solution was added gradually to the first solution. Afteraddition the reaction mixture was heated to 45° C. After 20 hours, thereaction mixture was concentrated under reduced pressure before addingethyl acetate (1 L) followed by 2 N HCl (500 mL). After mixing, thelayers were separated and the organic phase was washed sequentially with2 N HCl (500 mL), saturated sodium bicarbonate (500 mL), and water (500mL). The organic phase was concentrated under reduced pressure, theresidue taken up in ethyl acetate (1000 mL) and concentrated again toafford the title compound (104.94 g).

MS (ES+) 257.2 [M+1]⁺. ¹H NMR showed product as a 7.5:1 keto:enolmixture. For the keto tautomer: ¹H NMR (500 MHz, CDCl₃) δ ppm 7.85 (d,J=2.93 Hz, 1H) 7.45 (dd, J=8.90, 2.81 Hz, 1H) 6.92 (d, J=8.78 Hz, 1H)4.18 (q, J=7.16 Hz, 2H) 3.95 (s, 2H) 3.90 (s, 3H) 1.24 (t, J=7.07 Hz,3H).

Preparation 2

(Z)-Ethyl3-((2-amino-2-oxoethyl)amino)-3-(5-chloro-2-methoxyphenyl)acrylate

A 5-L reaction vessel was charged with methanol (3.3 L), sodiummethoxide (102.4 g, 1.8 moles), and glycinamide hydrochloride (202 g,1.8 moles). The mixture was heated at 65° C. for 1 hour before coolingto 50° C. and adding acetic acid (514.25 mmoles, 30.88 g, 29.47 mL) andethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (300 g, 1.03 mole).After heating to reflux for 16 hours, the reaction mixture was stirredas it was cooled to 10° C. After 30 min the resulting solid wascollected by vacuum filtration, pulling dry to form a cake that wasdried in a vacuum oven (20 mm Hg, 65° C.) for 14 hours to afford thetitle compound (339.4 g).

MS (ES+) 313.2 [M+1]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.80 (t, J=5.00Hz, 1H) 7.47 (dd, J=8.90, 2.81 Hz, 1H) 7.27 (br. s., 1H) 7.22 (d, J=2.68Hz, 1H) 7.14 (d, J=8.78 Hz, 1H) 7.09 (br. s., 1H) 4.30 (s, 1H) 4.03 (q,J=7.07 Hz, 2H) 3.80 (s, 3H) 3.56 (br. s., 1H) 3.45 (br. s., 1H) 1.18 (t,J=7.07 Hz, 3H).

Example 1

2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide

A reaction vessel equipped with an efficient stirrer was charged with(Z)-ethyl3-((2-amino-2-oxoethyl)amino)-3-(5-chloro-2-methoxyphenyl)acrylate (15g, 50.2 mmol), butyl acetate (150 mL) and trimethylsilyl isothiocyanate(160.7 mmole, 21.1 g, 22.7 mL) and the mixture was heated to reflux.After 15 hours, the mixture was cooled to 30° C. and treated with 1 Naqueous sodium hydroxide (112.5 mL, 112.5 mmoles). After 30 min, theorganic layer was separated and extracted with another portion of 1 Nsodium hydroxide (37.5 mL, 37.5 mmoles). The combined aqueous phaseswere extracted twice with dichloromethane (2×45 mL), filtered, andtreated with 6N HCl until a pH of 2.5 was achieved. After stirring for 1hour, the resulting solid was isolated by vacuum filtration, resuspendedin 100 mL of a 1:1 methanol-water solution, heated with stirring at 50°C. for 2 hours, and cooled to room temperature before collecting thesolid by vacuum filtration, pulling dry and drying in a vacuum oven (20mm Hg, 50° C.) for 12 hours to afford 8.7 g of the desired product as atan solid.

MS (ES+) 326.0 [M+1]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.85 (s, 1H)7.57 (dd, J=9.03, 2.68 Hz, 1H) 7.33 (s, 1H) 7.17-7.23 (m, 2H) 7.10 (s,1H) 5.89 (d, J=1.71 Hz, 1H) 5.41 (br. s, 1H) 3.89 (br. s, 1H) 3.84 (s,3H).

Alternative Preparation of Example 1

2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide

A slurry of (Z)-ethyl3-((2-amino-2-oxoethyl)amino)-3-(5-chloro-2-methoxyphenyl)acrylate (20g, 63 mmol) in a mixture of butyl acetate (140 mL) and DMF (38 mL) wastreated with trimethylsilyl isothiocyanate (16.8 g, 125 mmol) and themixture was heated at 115-120° C. for 5-6 hours. The mixture was cooledto 0-5° C., butyl acetate (100 mL) was added and the mixture wasslurried for 8 hours. The formed solids were filtered, and the filtercake was washed with butyl acetate (2×100 mL). The solid was dried in avacuum oven at 50° C. for 12 hours to a tan solid. The solid wasdissolved in a 5:1 mixture of DMF and water at room temperature andadditional water was added slowly to crystallize the material. Theslurry was cooled to 10° C. and stirred for 8 hours, followed byfiltration and washing with water. The filter cake was dried in a vacuumoven at 50° C. for 8 hours. The solid was dissolved in a 1:1 mixture ofmethanol and water and the slurry was heated to 50° C. and held at thistemperature for 2 hours. After cooling to 10° C. over 30 minutes, theslurry was held at this temperature for 1 hour, filtered and washed withwater and dried in a vacuum oven at 50° C. for 8 hours to give the titlecompound as a white solid.

MS (ES+) 326.0 [M+1]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.85 (s, 1H)7.57 (dd, J=9.03, 2.68 Hz, 1H) 7.33 (s, 1H) 7.17-7.23 (m, 2H) 7.10 (s,1H) 5.89 (d, J=1.71 Hz, 1H) 5.41 (br. s, 1H) 3.89 (br. s, 1H) 3.84 (s,3H).

Preparation 3

Sodium 1-(2,5-dimethoxyphenyl)-3-ethoxy-3-oxoprop-1-en-1-olate

A 20-L reaction vessel was charged with magnesium ethoxide (3.61 moles;413.52 g) and THF (6.6 L), and the resulting mixture was stirred asethyl hydrogen malonate (7.23 moles; 888.89 mL; 994.67 g; diluted with20 mL of THF) was added and the mixture was heated at 45° C. for 4hours. Meanwhile, a 20 L reactor was charged with 2,5-dimethoxybenzoicacid (3.29 moles; 600.00 g) and THF (3.6 L). To this mixture stirring atroom temperature was added 1,1′-carbonyldiimidazole (3.61 moles; 585.98g) in portions to avoid excess foaming. After stirring for 3 hours atroom temperature the second solution was added gradually to the firstsolution. After addition the reaction mixture was heated to 45° C. After20 hours, the reaction mixture was concentrated under reduced pressurebefore adding ethyl acetate (6 L) followed by 2 N HCl (3 L). Aftermixing, the layers were separated and the organic phase was washedsequentially with 2 N HCl (3 L), saturated sodium bicarbonate (3 L), andwater (3 L). The organic phase was concentrated under reduced pressure,the residue taken up in ethyl acetate (6 L) and concentrated again toafford an oil, which was transferred to a 20 L reaction vessel with 5 Lof ethyl acetate and treated with sodium methoxide (3.45 moles; 793.00mL of a 4.35 M solution in methanol). After stirring at room temperaturefor 3 hours, an additional 6 L of ethyl acetate was added and the solidcollected by vacuum filtration and dried overnight in a vacuum oven at40° C. to give 661 grams of the title product.

MS (ES+) 253.1 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.92 (d, J=3.0Hz, 1H) 6.84 (d, J=8.8 Hz, 1H) 6.73 (dd, J=8.8, 3.0 Hz, 1H) 4.67 (s, 1H)3.88 (q, J=7.0 Hz, 2H) 3.67 (s, 6H) 1.12 (t, J=7.0 Hz, 3H).

Preparation 4

(Z)-Ethyl 3-((2-amino-2-oxoethyl)amino)-3-(2,5-dimethoxyphenyl)acrylate

A 5-L reaction vessel was charged with methanol (3.3 L), sodiummethoxide (102.4 g, 1.8 moles), and glycinamide hydrochloride (202 g,1.8 moles). The mixture was heated at 65° C. for 1 hour before coolingto 50° C. and adding acetic acid (514.25 mmoles, 30.88 g, 29.47 mL) andethyl 3-(2,5-dimethoxyphenyl)-3-oxopropanoate (300 g, 1.03 mole). Afterheating at reflux for 16 hours, the reaction mixture was stirred as itwas cooled to 10° C. After 30 min the resulting solid was collected byvacuum filtration, pulling dry to form a cake that was dried in a vacuumoven (20 mm Hg, 65° C.) for 14 hours to afford the title compound (339.4g).

MS (ES+) 309.1 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.84 (t, J=4.7Hz, 1H) 7.36 (s, 1H) 7.09 (s, 1H) 7.02 (d, J=8.9 Hz, 1H) 6.97 (dd,J=8.9, 2.8 Hz, 1H) 6.74 (d, J=2.8 Hz, 1H) 4.31 (s, 1H) 4.03 (q, J=7.1Hz, 2H) 3.74 (s, 6H) 3.58 (br. s., 1H) 3.47 (br. s., 1H) 1.18 (t, J=7.1Hz, 3H).

Example 2

2-(6-(2,5-Dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide

A 5-L reaction vessel equipped with an efficient stirrer was chargedwith (Z)-ethyl34(2-amino-2-oxoethyl)amino)-3-(2,5-dimethoxyphenyl)acrylate (1.30moles; 400.00 g), butyl acetate (3.4 L) and trimethylsilylisothiocyanate (4.15 moles; 585.67 mL; 544.96 g) and the mixture washeated to reflux. After 16 hours, the mixture was cooled to 40° C. andtreated with 2 N aqueous sodium hydroxide (1.95 L). The organic layerwas separated and extracted with another portion of 2 N sodium hydroxide(0.325 L). The combined aqueous phases were filtered, extracted twicewith dichloromethane (2×1.6 L), and added slowly to a well-stirred 3Naqueous HCl solution (1.3 L) at room temperature. After stirring for 30min, the resulting solid was isolated by vacuum filtration, rinsing withwater, and pulled dry to afford a water wet cake (640 g). The cake wasdissolved in dimethylformamide (2.4 L) at 90° C. and stirred as water (2L) was added slowly to the solution. The mixture was cooled gradually toroom temperature and the resulting solid isolated by vacuum filtration,rinsing with water and pulling dry to afford 245 g of solid. This solidwas then suspended in 1.25 L of methanol and stirred as 1.25 L of waterwas added. The mixture was heated with stirring at 50° C. for 2 hours,and then cooled to 10° C. for 2 hours before collecting the solid byvacuum filtration, pulling dry before drying in a vacuum oven (20 mm Hg,60 C) to afford the desired product.

MS (ES+) 322.2 [M+1]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.80 (5, 1H)7.32 (br. s., 1H) 7.06-7.11 (m, 2H) 7.06 (br. s., 1H) 6.74-6.77 (m, 1H)5.82 (d, J=2.20 Hz, 1H) 5.37 (br. s., 1H) 3.88 (br. s., 1H) 3.78 (s, 3H)3.70 (s, 3H).

B. Methyl Ketone Route Section Preparation 5

Methyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate

To a three-necked round-bottomed flask equipped with a mechanicalstirrer under N₂ was added potassium tert-butoxide (1M in THF, 108.77mL, 108.77 mmol), followed by a solution of 2,4-dimethoxyacetophenone(10.00 g, 54.38 mmol) and dimethyl carbonate (13.93 mL, 163.15 mmol) inmethyl tert-butyl ether (50 mL) dropwise via an addition funnel over 1.5hours. During addition, reaction turned from a initial cloudy yellowmixture to a thick red-orange slurry. Reaction mixture was stirred atroom temperature overnight. Aqueous citric acid solution (0.5 N, 110.95mL, 54.39 mmol) was added via addition funnel to quench the reaction.Exotherm was observed during quenching and solids dissolved to give anorange mixture. The layers were separated and the aqueous layer wasextracted with methyl tert-butyl ether (2×25 mL). The combined organicextracts were concentrated to low volume. Heptane (50 mL) was added andbrown solids precipitated. The resulting slurry was stirred under N₂overnight at room temperature. Solids were filtered and dried under N₂to give the title compound (11.05 g, 85% yield) as a beige coloredpowder.

MS (ES+) 239.1 [M+1]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.95 (d, J=8.78 Hz, 1H)6.57 (dd, J=8.78, 2.20 Hz, 1H) 6.45 (d, J=2.20 Hz, 1H) 3.94 (s, 2H) 3.88(s, 3H) 3.87 (s, 3H) 3.73 (s, 3H).

Preparation 6

(Z)-Methyl 3-(2,4-dimethoxyphenyl)-3-(2-hydroxyethyl)amino)acrylate

To a mixture of methyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate (3.50 g,14.69 mmol) and acetic acid (0.17 mL, 2.94 mmol) in i-PrOH (70 mL) wasadded ethanolamine (0.88 mL, 14.69 mmol) and the reaction mixture washeated to 83° C. Additional ethanolamine (0.88 mL, 14.69 mmol) was addedto the reaction mixture at two, four and six hours. After stirring at80° C. for 48 hours, the reaction mixture was cooled and concentratedunder reduced pressure before the residue was suspended in equal partsof a saturated sodium bicarbonate solution and water under N₂. Afterstirring overnight, the solids were collected by vacuum filtration anddried in a vacuum oven at 30° C. overnight to afford the title compound(2.72 g, 63%) as a beige colored power.

¹H NMR (400 MHz, CDCl₃) δ 8.77 (t, J=5.37 Hz, 1H) 7.13 (d, J=8.29 Hz,1H) 6.47-6.52 (m, 2H) 4.53 (s, 1H) 3.84 (s, 3H) 3.82 (s, 3H) 3.66 (s,3H) 3.61 (td, J=5.45, 5.45 Hz, 2H) 3.15 (td, J=5.53, 5.53 Hz, 2H).

Example 3

6-(2,4-Dimethoxyphenyl)-1-(2-hydroxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one

To a solution of (Z)-methyl3-(2,4-dimethoxyphenyl)-3-((2-hydroxyethyl)amino)acrylate (9.50 g, 33.77mmol) in 2-MeTHF (100 mL) was added (trimethylsilyl)isothiocyanate(23.80 mL, 168.79 mmol), and the reaction mixture was heated at 85° C.After stirring overnight, the reaction mixture was cooled, extractedwith an aqueous 1N NaOH solution (1×250 mL, then 1×50 mL), the combinedaqueous layers were washed with CH₂Cl₂ (2×50 mL) and the aqueous phaseacidified to pH 4 with concentrated HCl. The resulting solids werefiltered, washed with water (2×50 mL) and dried under N₂ overnight togive a light yellow powder. The product was dissolved in DMF (70 mL) at90° C., and then water (80 mL) was added to this hot solution. Afterallowing to cool to room temperature and stirring overnight, the solidswere collected by vacuum filtration, washed with water and dried underhigh vacuum to provide the title compound (6.7 g, 61%) as an off-whitepowder.

MS (ES+) 309.1 [M+1]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.68 (s, 1H)7.24 (d, J=8.29 Hz, 1H) 6.69 (d, J=2.44 Hz, 1H) 6.65 (dd, J=8.42, 2.32Hz, 1H) 5.70 (d, J=2.20 Hz, 1H) 4.69 (t, J=4.88 Hz, 1H) 4.50 (ddd,J=13.42, 7.07, 4.15 Hz, 1H) 3.83 (s, 3H) 3.82 (s, 3H) 3.59 (dt, J=13.42,7.32 Hz, 1H) 3.46-3.55 (m, 1H) 3.38-3.46 (m, 1H).

C. Aryl Halide Route Section Preparation 7

(Z,E)-Ethyl 3-(2,6-dimethoxypyridin-3-yl)-3-ethoxyacrylate

Bis(tri-t-butylphosphine)palladium (47 mg, 0.092 mmol)) and lithiumchloride (292 mg, 0.27 mmol) were added to a flask equipped with refluxcondenser, and the apparatus was evacuated under vacuum and refilledwith N₂ several times. To this flask was added via cannula a degassedsolution of anhydrous 1,4-dioxane (8 mL) under N₂, followed by3-bromo-2,6-dimethoxypyridine (500 mg, 2.29 mmol),N,N-dicyclohexylmethylamine (540 uL, 2.52 mmol) and ethyl3-ethoxyacrylate (1.0 mL, 6.88 mmol), and the resulting orange solutionwas heated to 110° C. After 20 hours, the reaction mixture was cooled toroom temperature, quenched with water and diluted with EtOAc. The layerswere separated and the aqueous layer was extracted with EtOAc. Thecombined organic extracts were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by chromatography onsilica eluting with 0-50% EtOAc/heptane to yield the title compound (604mg, 94%) as an amber oil. ¹H NMR showed the product to be composed of a2.5:1 mixture of E/Z isomers.

Preparation 8

Ethyl 3-(2,6-dimethoxypyridin-3-yl)-3-oxopropanoate

To a solution of ethyl 3-(2,6-dimethoxypyridin-3-yl)-3-ethoxyacrylate(600 mg, 2.13 mmol) in CH₂Cl₂ (18 mL) was gradually added 3N aqueous HCl(3.5 mL). The reaction mixture was stirred at room temperature for 2hours, then carefully added to a saturated sodium bicarbonate solution(30 mL). The layers were separated and the aqueous layer was extractedwith CH₂Cl₂. The combined organic extracts were passed though a plug ofcotton to dry and concentrated in vacuo. The resulting oil was purifiedby flash chromatography (0-60% EtOAc/heptanes) to provide the titlecompound (515 mg, 95% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.22 (d, J=8.59 Hz, 1H) 6.40 (d, J=8.39Hz, 1H) 4.20 (q, J=7.03 Hz, 2H) 4.03 (s, 3H) 3.99 (s, 3H) 3.94 (s, 2H)1.26 (t, J=7.13 Hz, 3H).

D. Amine Deprotection Route and Derivativation Preparation 9

(Z)-Ethyl3-(2,6-dimethoxypyridin-3-yl)-3-((2-hydroxyethyl)amino)acrylate

To a solution of ethyl 3-(2,6-dimethoxypyridin-3-yl)-3-oxopropanoate(500 mg, 1.97 mmol) in EtOH (4 mL) was added 2-aminoethanol (0.60 mL,9.9 mmol) followed by acetic acid (0.63 mL, 9.9 mmol). The reactionmixture was heated to 90° C. for 16 hours, cooled to room temperatureand concentrated in vacuo. The residue was partitioned between EtOAc andwater. The organic layer was concentrated in vacuo and the crudematerial was purified by chromatography on silica eluting with 20-80%EtOAc/heptane to provide the title compound (573 mg, 98%) as a cleargum.

MS (ES+) 297.3 [M+1]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.75 (br. s., 1H) 7.44(d, J=8.05 Hz, 1H) 6.34 (d, J=8.05 Hz, 1H) 4.51 (s, 1H) 4.14 (q, J=7.16Hz, 2H) 3.97 (s, 3H) 3.95 (s, 3H) 3.64 (td, J=5.53, 5.53 Hz, 2H) 3.17(td, J=5.53, 5.53 Hz, 2H) 1.96 (br. s., 1H) 1.27 (t, J=7.07 Hz, 3H).

Example 4

6-(2,6-Dimethoxypyridin-3-yl)-1-(2-hydroxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one

To a solution of (Z)-ethyl3-(2,6-dimethoxypyridin-3-yl)-3-((2-hydroxyethyl)amino)acrylate (100 mg,0.34 mmol) in 2-MeTHF (1.0 mL) was added (trimethylsilyl)isothiocyanate(0.30 mL, 2.0 mmol) and the reaction mixture was heated at 80° C. for 4hours. The cooled reaction mixture was diluted with EtOAc and washedwith a saturated aqueous sodium bicarbonate solution. The layers wereseparated and the organic layer was concentrated in vacuo. The residuewas triturated with MeOH and the resulting solids were collected byvacuum filtration to give the title compound (16 mg, 16%) as a whitesolid.

MS (ES+) 310.2 [M+1]⁺. ¹H NMR (500 MHz, CD₃OD) δ 7.60 (d, J=8.29 Hz, 1H)6.47 (d, J=8.05 Hz, 1H) 5.76 (s, 1H) 4.66-4.75 (m, 1H) 4.01 (s, 3H) 3.98(s, 3H) 3.77-3.85 (m, 2H) 3.57-3.63 (m, 1H)

Preparation 10

(Z)-ethyl3-(2-(tert-butoxycarbonylamino)ethylamino)-3-(2,4-dimethoxyphenyl)acrylate

A solution of ethyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate (41.91 g,166 mmol), tert-butyl 12-aminoethylcarbamate (54.7 g, 342 mmol), andacetic acid (16.14 g, 269 mmol) in ethanol (180 mL) was heated at refluxfor 5.3 h. After removal of most of the solvent by rotary evaporation,the resulting oil was partitioned between EtOAc (ca. 300 mL) and 10%(w/v) aq. ammonium chloride. The EtOAc layer was separated and thenwashed with water, 10% (w/v) aq. ammonium chloride (3 mL), and brine (10mL). The EtOAc layer was washed with sat. aq. sodium bicarbonate, brine(6 mL) was added, and the emulsion was allowed to settle. The EtOAclayer was finally washed with brine and dried over sodium sulfate.Evaporation of the EtOAc layer's volatile components afforded a viscous,amber taffy (62.3 g, 95%). This crude product was used without furtherpurification.

LCMS (ESI) m/z: 395.4 [M+H] (100%). ¹H NMR (500 MHz, CDCl₃) δ 1.27 (t,J=7.1 Hz, 3H), 1.43 (s, 9H), 3.03-3.21 (m, 4H), 3.83 (s, 6H), 4.14 (q,J=7.1 Hz, 2H), 4.51 (s, 1H), 4.88 (br. s., 1H), 6.47 (d, J=1.7 Hz, 1H),6.50 (dd, J=8.4, 1.8 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 8.65 (br. s., 1H).

Example 5

tert-butyl2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethylcarbamate

(Trimethylsilyl)isothocyanate (66 mL, 470 mmol) was added to a solutionof (Z)-ethyl3-(2-(tert-butoxycarbonylamino)ethylamino)-3-(2,4-dimethoxyphenyl)acrylate(62.3 g, 158 mmol) in 2-MeTHF (160 mL). After heating at reflux undernitrogen for 15 h, the reaction mixture was cooled to ambienttemperature and quenched by cautious addition of sat. aq. sodiumbicarbonate (470 mL). The r×n. mixture was extracted withdichloromethane, and the aq. layer was twice more extracted withdichloromethane. The combined organic layers were dried over sodiumsulfate and evaporated to afford a yellow-amber foam, which was purifiedby chromatography on silica eluting with 0-80% ethyl acetate in heptanesto afford 49.2 g of solid. These solids were re-suspended in 1:1EtOAc/heptane at 70° C. for 1 h and then at r.t. for another 1 h. Theresulting solids were isolated by vacuum filtration, rinsing withadditional 1:1 EtOAc/heptane, and pulled dry on the filter. The titlecompound was obtained as a white, microcrystalline solid (38.3 g, 59.5%yield).

LCMS (ESI) m/z: 408.3 [M+H] (100%). ¹H NMR (500 MHz, CDCl₃, majorrotamer) δ 1.40 (s, 9H), 3.23-3.45 (m, 2H), 3.74 (dt, J=14.4, 5.4 Hz,1H), 3.84 (s, 3H), 3.87 (s, 3H), 4.68-4.81 (m, 2H), 5.81 (d, J=2.2 Hz,1H), 6.51 (d, J=2.2 Hz, 1H), 6.59 (dd, J=8.4, 2.1 Hz, 1H), 7.26 (d,J=8.4 Hz, 1H), 9.58 (br. s., 1H).

Example 6

1-(2-aminoethyl)-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-onehydrochloride

To a solution of EtOH (50 mL, 860 mmol) in EtOAc (390 mL), cooled in anice/water bath, was slowly added acetyl chloride (55 mL, 770 mmol) over3 minutes. After 5 minutes the cooling bath was removed, and afterstirring for 45 min, the solution was added to tert-butyl2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethylcarbamate(31.7 g, 77.8 mmol). A suspension formed over time, and after stirringfor 5 h, the solid was collected by vacuum filtration, rinsing withEtOAc. The solid was pulled dry and dried further under vacuum to afford26.6 g (99.3%) of the desired product as a colorless solid.

LCMS (ESI) m/z: 291.3 [M−NH3+H] (100%), 308.3 [M+H] (33%), 615.5 [2M+H](2.3%). ¹H NMR (500 MHz, CD3OD) δ 3.06 (ddd, J=12.9, 7.8, 5.9 Hz, 1H),3.12 (ddd, J=12.9, 7.7, 6.4 Hz, 1H), 3.87 (s, 3H), 3.89 (s, 3H), 4.14(ddd, J=14.0, 7.8, 5.9 Hz, 1H), 4.82 (ddd, J=14.0, 7.7, 6.4 Hz, 1H),5.80 (s, 1H), 6.70 (dd, J=8.3, 2.2 Hz, 1H), 6.73 (d, J=2.2 Hz, 1H), 7.27(d, J=8.3 Hz, 1H).

Example 7

2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl)guanidine

Diisopropylethylamine (0.22 mL, 1.3 mmol) was added to a suspension of1-(2-aminoethyl)-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-onehydrochloride (181.6 mg, 0.528 mmol) (the product of Example 6) and1H-pyrazole-1-carboxamidine hydrochloride (90.6 mg, 0.618 mmol) in DMF(0.55 mL). After heating for 1 h at 55° C., the reaction mixture wascooled to ambient temperature, diluted with EtOH (1.6 mL), and the solidproduct collected by vacuum filtration, rinsing with additional EtOH.The isolated solid was re-suspended in EtOH (2.1 mL) for 3 h at r.t.before being collected again by vacuum filtration and rinsing withadditional EtOH. The desired product was obtained, after drying, as acolorless solid. Solubility data for this product is consistent with itbeing in its zwitterionic form.

¹H NMR (500 MHz, CD3OD+2 drops 20. % DCI in D2O) δ 3.31-3.37 (m, 1H),3.67 (ddd, J=14.8, 8.6, 5.9 Hz, 1H), 3.88-3.99 (m, 1H), 3.90 (s, 6H),4.66-4.77 (m, 1H), 5.80 (s, 1H), 6.69 (d, J=2.2 Hz, 1H), 6.71 (dd,J=8.3, 2.2 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H).

2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl)guanidinehydrochloride

The product from the above reaction (116.3 mg, 0.333 mmol) was suspendedin dioxane and treated with a 4.0 M HCl/dioxane solution (0.30 mL, 1.2mmol). After thorough vortexing, the volatile components of the mixturewere removed to afford a white solid (130.6 mg, 0.338 mmol). LCMS (ESI)m/z: 350.1 [M+H] (100%).

Preparation 11

tert-butyl2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethylamino)-2-oxoethylcarbamate

To a solution of1-(2-aminoethyl)-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-onehydrochloride (123 mg, 0.4 mmol)(the product of Example 6) in drymethylene chloride (4 mL) was addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (182 mg, 0.48 mmol) andtert-butoxycarbonylamino-acetic acid (70 mg, 0.4 mmol) anddiisoproplyethylamine (336 mg, 1.6 mmol). After stirring overnight at RTthe reaction mixture was concentrated under reduced pressure and theresidue purified by preparative thin layer chromatography (1:1 petroleumether:ethyl acetate) to provide tert-butyl2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethylamino)-2-oxoethylcarbamate(120 mg, 65%).

Example 8

2-amino-N-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl)acetamidehydrochloride

To a solution of tert-butyl2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethylamino)-2-oxoethylcarbamate(70 mg, 0.15 mmol) in ethyl acetate (2 mL) was added a solution of HClin ethyl acetate (2 mL). After stirring at room temperature for 4 hours,the reaction mixture was concentrated under reduced pressure to affordthe desired2-amino-N-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl)acetamidehydrochloride as a solid (65 mg, 100%).

II. 6-Iodo-Thiouracil Route Section Preparation 12

N-((2-Methoxyethyl)carbamothioyl)benzamide

2-Methoxyethylamine (17.7 mL, 202.2 mmol) was added dropwise over 30minutes to a stirring solution of benzoylisothiocyanate (30.00 g, 183.8mmol) in CH₂Cl₂ (300 mL) at room temperature under argon and the mixturewas stirred at room temperature for 16 hours. The mixture was washedsequentially with 10% aqueous citric acid (75 mL), water (75 mL) andbrine (75 mL), dried over MgSO₄ and concentrated in vacuo. The resultingyellow oil solidified on standing to give the title compound (41.85 g,96%). The material was used directly in the next step without furtherpurification.

Preparation 13

1-(2-Methoxyethyl)thiourea

A solution of N-((2-methoxyethyl)carbamothioyl)benzamide (41.82 g, 175.5mmol), potassium carbonate (24.25 g, 175.5 mmol) in MeOH (200 mL) andwater (200 mL) was stirred at room temperature for 16 hours. The mixturewas concentrated in vacuo and the aqueous layer was extracted with EtOAc(5×100 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo. The resulting yellow oil solidified on standingto provide the title compound (21.38 g, 91%). The material was useddirectly in the next step without further purification.

MS (ES+) 135.1 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃) δ 6.66 (br. s., 1H) 6.46(br. s., 1H) 5.81 (br. s., 1H) 3.80 (br. s., 2H) 3.48-3.65 (m, 2H) 3.40(s, 3H).

Preparation 14

1-(2-Methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one

To a stirring solution of 1-(2-methoxyethyl)thiourea (21.38 g, 159.3mmol) and ethyl 3,3-diethoxypropanoate (46.5 mL, 239.0 mmol) in MeOH(300 mL) was added a freshly prepared solution of 0.96N sodium methoxidein MeOH (250 mL, 239.0 mmol) dropwise over 30 minutes at roomtemperature under argon. The reaction mixture was heated to 60° C. for45 minutes and cooled to room temperature. Solvent was removed underreduced pressure and toluene (250 mL) was added to the residue. Themixture was stirred at reflux for an additional 3 hours and then cooledto room temperature. Water (200 mL) was added and the layers wereseparated. The aqueous layer was washed with CH₂Cl₂ (50 mL), neutralizedwith 2N aqueous HCl and extracted with CH₂Cl₂ (3×200 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Theresidue was recrystallized from i-PrOH (200 mL) to give the titlecompound (13.3 g, 45%) as a light yellow crystalline solid.

MS (ES+) 187.1 (M+1)⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.81 (br. s., 1H) 7.39(d, J=7.81 Hz, 1H) 5.94 (d, J=8.00 Hz, 1H) 4.39 (dd, J=5.27, 4.49 Hz,2H) 3.73 (dd, J=5.07, 4.29 Hz, 2H) 3.36 (s, 3H).

Preparation 15

6-Iodo-1-(2-methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one

To a stirring solution of diisopropylamine (8.3 mL, 59.10 mmol) in THF(50 mL) was added n-butyl lithium (2N in hexanes, 30.0 mL, 60.0 mmol)dropwise at −78° C. under argon. The reaction mixture was slowly warmedto −20° C. and then cooled to −78° C. A solution of1-(2-methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (5.0 g, 26.85mmol) in THF (50 mL) was added dropwise at −78° C. The reaction mixturewas slowly warmed to −10° C. over 1 hour and then cooled to −78° C. Asolution of iodine (15.0 g, 59.07 mmol) in THF (50 mL) was added at −78°C. and the reaction mixture was stirred at room temperature for 20hours. Reaction was diluted with saturated aqueous ammonium chloride(200 mL) and the organic solvents were removed under reduced pressure.The aqueous residue was acidified to pH 4 with 1N aqueous HCl andextracted with CH₂Cl₂ (3×300 mL, 1×200 mL). The combined organic layerswere washed with 10% aqueous sodium thiosulfate solution (400 mL), brine(300 mL), dried over MgSO₄ and concentrated in vacuo. The resultingresidue was stirred in CH₂Cl₂ at room temperature and solids werecollected by filtration to give the title compound (9.05 g, 54%) as apale brown solid. The filtrate was concentrated and purified by flashchromatography (0-25% CH₂Cl₂/EtOAc) to afford a second batch of thetitle compound (3.10 g, 18%) as a cream colored solid (72% combinedyield).

MS (ES+) 313.0 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.88 (br. s., 1H) 6.70(s, 1H) 4.88 (br. s., 2H) 3.78 (t, J=6.05 Hz, 2H) 3.40 (s, 3H).

Preparation 16

6-Iodo-1-(2-methoxyethyl)-2-(methylthio)pyrimidin-4(1H)-one

To a stirring solution of6-iodo-1-(2-methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (9.00g, 28.83 mmol) in MeCN (200 mL) was added diisopropylethylamine (5.0 mL,28.83 mmol) and iodomethane (9.0 mL, 144.17 mmol). The reaction mixturewas stirred at room temperature for 18 hours, and concentrated in vacuo.The residue was partitioned portioned between CH₂Cl₂ (200 mL) and 1Naqueous HCl (100 mL). The layers were separated and the organic layerwas washed with brine (100 mL), dried over MgSO₄ and concentrated invacuo. The resulting residue was purified by hot trituration withCH₂Cl₂/heptane to give the title compound (4.05 g, 43%) as a creamcolored solid.

MS (ES+) 327.0 [M+1]⁺. ¹H NMR (500 MHz, CDCl₃) δ 6.77 (s, 1H) 4.42 (t,J=6.34 Hz, 2H) 3.69 (t, J=6.34 Hz, 2H) 3.40 (s, 3H) 2.58 (s, 3H).

IIA. Suzuki Route Section Preparation 17

6-(2,5-dimethoxyphenyl)-1-(2-methoxyethyl)-2-(methylthio)pyrimidin-4(1H)-one

To a mixture of6-iodo-1-(2-methoxyethyl)-2-(methylthio)pyrimidin-4(1H)-one (100 mg,0.31 mmol), (2,5-dimethoxyphenyl)boronic acid (0.37 mmol, 1.2 equiv.)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14 mg,0.017 mmol, 0.05 equiv) was added degassed 1,4-dioxane (2 mL), followedby a degassed solution of sodium carbonate (65 mg, 0.61 mmol) in water(0.7 mL). This reaction mixture was subjected to microwave irradiationat 120° C. for 30 minutes and the crude reaction mixture was useddirectly in the next step.

Example 9

6-(2,5-dimethoxyphenyl)-1-(2-methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one

Ammonium sulfide (1 mL, 14.63 mmol) and pyridine (1 mL, 12.41 mmol) wereadded to the crude reaction mixture obtained from the previous Suzukicoupling reaction (0.31 mmol theoretical yield), and the mixture wassubjected to microwave irradiation at 75° C. for 30 minutes. Thereaction mixture was cooled to room temperature, taken up in CH₂Cl₂ (10mL) and water (10 mL), then basified with 2N NaOH. The layers wereseparated and the aqueous layer was washed with CH₂Cl₂ (2×10 mL). Theaqueous layer was then acidified to pH 6 with 2N aqueous HCl andextracted with EtOAc (3×10 mL). The combined organic extracts were driedover MgSO₄ and concentrated in vacuo.

The crude reaction mixture was purified by flash chromatography to givethe desired product (38 mg, 38% over two steps) as solid.

MS (ES+) 323.1 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.14 (br. s., 1H),7.01 (dd, J=8.90, 3.10 Hz, 1H), 6.89 (d, J=9.16 Hz, 1H), 6.80 (d, J=3.21Hz, 1H), 5.84 (d, J=1.83 Hz, 1H), 4.70 (dt, J=13.74, 4.35 Hz, 1H),3.83-3.92 (m, 1H), 3.78-3.82 (m, 6H), 3.73-3.79 (m, 1H), 3.44 (ddd,J=9.96, 5.84, 3.89 Hz, 1H), 3.16 (s, 3H)

II B. Neqishi Route Section Preparation 18

1-(2-Methoxyethyl)-2-(methylthio)-6-(pyridin-2-yl)pyrimidin-4(1H)-one

n-Butyl lithium (2.0 M, 0.32 mL, 0.64 mmol) was slowly added to2-bromopyridine (0.058 mL, 0.61 mmol) in dry THF (2 mL) at −78° C. After30 minutes, anhydrous zinc chloride (92 mg, 0.67 mmol) was added and thereaction mixture was stirred for an additional 30 minutes as it warmedto room temperature. To the reaction mixture was added6-iodo-1-(2-methoxyethyl)-2-(methylthio)pyrimidin-4(1H)-one (200 mg,0.61 mmol), followed by tris(dibenzylideneacetone)dipalladium(0) (27 mg,0.03 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (26 mg, 0.06mmol) and DMF (2 mL), and the reaction mixture was then heated to 80° C.After stirring overnight, the product was extracted with EtOAc (3×10 mL)and washed with water (3×10 mL). The aqueous was then acidified with 2MHCl to pH 4 and the product was extracted with DCM (3×10 mL) and driedover MgSO₄. The solvent was removed in vacuo to give an orange oil (100mg) as a mixture of1-(2-methoxyethyl)-2-(methylthio)-6-(pyridin-2-yl)pyrimidin-4(1H)-one(37%) and 1-(2-methoxyethyl)-2-(methylthio)pyrimidin-4(1H)-one (32%).

Example 10

1-(2-Methoxyethyl)-6-(pyridin-2-yl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one

A mixture of crude1-(2-methoxyethyl)-2-(methylthio)-6-(pyridin-2-yl)pyrimidin-4(1H)-one(100 mg, 0.36 mmol), ammonium sulfide solution (0.2 mL, 0.64 mmol) andpyridine (0.2 mL) was stirred in dioxane (2 mL) at 70° C. for 4 hours.The reaction mixture was diluted with water (10 mL), basified with 2MNaOH and washed with dichloromethane (3×10 mL). The aqueous layer wasacidified to pH 6 with 2M HCl and extracted with ethyl acetate (3×10mL). The combined organic layers were washed with water (3×10 mL), brine(3×10 mL), dried over MgSO₄ and concentrated in vacuo. The crudematerial was purified by mass directed automatic purification using anacidic method to give the product as a brown solid (3 mg, 3%).

MS (ES+) 264.07 [M+H]⁺. 1H NMR (400 MHz, CDCl3) δ 8.76 (br s, 1H), 7.92(br s, 1H), 7.48-7.54 (m, 2H), 7.32 (br d, 1H), 5.95 (br d, 1H), 4.65(br s, 2H), 3.64 (br s, 2H).

The following Examples of Table 2 were prepared from the correspondingcarboxylic acid to afford the intermediate beta-keto-ester as describedfor the Preparations in the Carboxylic Acid Route Section above followedby employing other methods described above in the I. Beta-Keto EsterRoute Section as well as standard methods and techniques known to thoseskilled in the art.

TABLE 2 Examples from Carboxylic Acid Route Ex- 1H NMR Spectral Data orample Compound Obs HPLC Retention Time and # Structure Name MassConditions 11

1-(2- aminoethyl)-6- (2- methoxyphenyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one hydrochloride 278.1 1H NMR (400 MHz, DMSO-d6) δ ppm 7.58-7.98(m, 3 H), 7.54 (td, J = 8.20, 1.60 Hz, 1 H), 7.35 (dd, J = 7.56, 1.60Hz, 1 H), 7.19 (d, J = 8.24 Hz, 1 H), 7.08 (t, J = 7.44 Hz, 1 H), 5.77(s, 1 H), 4.60 (ddd, J = 13.51, 7.79, 6.41 Hz, 1 H), 3.82-3.87 (m, 1 H),3.81 (s, 3 H), 2.76-2.91 (m, 2 H) 12

1-(2- hydroxyethyl)-6- (4- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 279.0 1H NMR (500 MHz, METHANOL-d4) δ ppm7.38 (d, J = 8.54 Hz, 2 H) 7.05 (d, J = 8.54 Hz, 2 H) 5.77 (s, 1 H) 4.37(t, J = 6.22 Hz, 2 H) 3.86 (s, 3 H) 3.74 (t, J = 6.34 Hz, 2 H) 13

4-[3-(2- methoxyethyl)- 6-oxo-2-thioxo- 1,2,3,6- tetrahydropyrimi-din-4- yl]benzonitrile 288.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.53(br. s, 1 H), 7.80 (d, J = 8.70 Hz, 2 H), 7.50 (d, J = 8.70 Hz, 2 H),5.80 (s, 1 H), 4.30 (br. s., 2 H), 3.65 (t, J = 5.04 Hz, 2 H), 3.21 (s,3 H) 14

1-(2- aminoethyl)-6- (2,3-dihydro-1- benzofuran-5- yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 290.0 1H NMR (300 MHz,DMSO-d6) δ ppm 12.82 (br. s., 1 H), 7.79 (br. s., 3 H), 7.38 (s, 1 H),7.24 (dd, J = 8.01, 1.74 Hz, 1 H), 6.90 (d, J = 8.36 Hz, 1 H), 5.76 (d,J = 2.09 Hz, 1 H), 4.61 (t, J = 8.71 Hz, 2 H), 4.34 (t, J = 8.01 Hz, 2H), 3.24 (t, J = 8.71 Hz, 2 H), 2.89-3.02 (m, 2 H) 15

6-(2,3-dihydro- 1-benzofuran-5- yl)-1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 291.0 1H NMR (300 MHz, DMSO-d6) δ ppm 12.68(br. s., 1 H), 7.34 (s, 1 H), 7.20 (d, J = 8.36 Hz, 1 H), 6.86 (d, J =8.36 Hz, 1 H), 5.70 (d, J = 2.09 Hz, 1 H), 4.75 (t, J = 5.57 Hz, 1 H),4.60 (t, J = 9.06 Hz, 2 H), 4.19 (t, J = 6.62 Hz, 2 H), 3.53 (td, J =5.60 Hz, 2 H), 3.23 (t, J = 8.71 Hz, 2 H) 16

6-(2,3-dihydro- 1-benzofuran-7- yl)-1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 291.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.50 (br. s., 1 H), 7.33 (d, J = 7.10 Hz, 1 H), 7.04 (d, J = 7.56 Hz, 1H), 6.95 (t, J = 7.56 Hz, 1 H), 5.86 (s, 1 H), 4.70-4.81 (m, 1 H), 4.64(t, J = 8.70 Hz, 2 H), 3.98- 4.10 (m, 1 H), 3.81-3.90 (m, 1 H),3.65-3.78 (m, 2 H), 3.30 (t, J = 8.70 Hz, 1 H), 1.86 (t, J = 5.95 Hz, 1H) 17

2-[6-(2- methoxyphenyl)- 4-oxo-2-thioxo- 3,4- dihydropyrimidin- 1(2H)-yl]acetamide 292.0 1H NMR (400 MHz, DMSO-d6) δ ppm 12.78 (br. s., 1 H),7.48 (td, J = 7.90, 1.60 Hz, 1 H), 7.26 (br. s., 1 H), 7.08-7.17 (m, 2H), 7.00 (t, J = 7.44 Hz, 1 H), 6.96 (br. s., 1 H), 5.76 (d, J = 2.06Hz, 1 H), 5.22-5.48 (m, 2 H), 3.80 (s, 3 H) 18

1-(3- aminopropyl)-6- (2- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 292.0 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.55 (ddd, J = 8.00, 8.00, 1.30 Hz, 1 H), 7.33 (dd, J= 7.42, 1.37 Hz, 1 H), 7.17 (d, J = 8.39 Hz, 1 H), 7.10 (dd, J = 7.40,7.40 Hz, 1 H), 5.78 (s, 1 H), 4.58 (dt, J = 15.13, 7.66 Hz, 1 H), 3.88(s, 3 H), 3.72-3.83 (m, 1 H), 2.73 (t, J = 7.81 Hz, 2 H), 1.94-2.07 (m,1 H), 1.75-1.88 (m, 1 H) 19

1-(2- aminoethyl)-6- (2-methoxy-5- methylpyridin-3- yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one trifluoroacetate 292.9 1H NMR (400 MHz,DMSO-d6): δ 12.99 (br, 1H), 8.27 (s, 1H), 7.81 (br, 3H), 7.74 (s, 1H),5.96 (s, 1H), 3.96-4.02 (m, 5H), 3.00 (m, 2H), 2.38 (s, 3H). 20

1-(2- methoxyethyl)- 6-(3- methoxypyridin- 2-yl)-2-thioxo- 2,3-dihydropyrimidin- 4(1H)-one 294.0 1H NMR (400 MHz, CHLOROFORM-d) δ ppm8.30 (dd, J = 4.81, 1.14 Hz, 1 H), 7.43 (dd, J = 8.70, 4.58 Hz, 1 H),7.35 (dd, J = 8.70, 1.37 Hz, 1 H), 5.92 (s, 1 H), 4.33 (br. s., 2 H),3.88 (s, 3 H), 3.55 (t, J = 6.41 Hz, 2 H), 3.13 (s, 3 H) 21

1-(2- hydroxyethyl)-6- (2-methoxy-6- methylpyridin-3- yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 294.1 1H NMR (400 MHz, DMSO-d6) δ ppm 12.73(br. s., 1 H), 7.62 (d, J = 7.56 Hz, 1 H), 6.97 (d, J = 7.33 Hz, 1 H),5.76 (s, 1 H), 4.69 (t, J = 5.38 Hz, 1 H), 4.43- 4.55 (m, 1 H), 3.86 (s,3 H), 3.44-3.60 (m, 3 H), 2.43 (s, 3 H) 22

1-(2- hydroxyethyl)-6- (3-methoxy-6- methylpyridin-2- yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 294.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.33 (d, J = 8.47 Hz, 1 H), 7.29 (d, J = 8.47 Hz, 1 H), 5.93 (s, 1 H),4.18-4.35 (m, 2 H), 3.91-3.98 (m, 2 H), 3.84 (s, 3 H), 2.54 (s, 3 H) 23

1-(2- methoxyethyl)- 6-(2- methoxypyridin- 3-yl)-2-thioxo- 2,3-dihydropyrimidin- 4(1H)-one 294.2 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.76 (br. s, 1 H), 8.32 (dd, J = 5.04, 1.83 Hz, 1 H), 7.56 (dd, J =7.33, 1.83 Hz, 1 H), 7.03 (dd, J = 7.33, 5.04 Hz, 1 H), 5.80 (s, 1 H),4.76 (dt, J = 13.74, 3.43 Hz, 1 H), 3.99 (s, 3 H), 3.69-3.86 (m, 2 H),3.40 (dt, J = 10.00, 4.20 Hz, 1 H), 3.15 (s, 3 H) 24

1-(2- hydroxyethyl)-6- [2- (methylthio)phen- yl]-2-thioxo- 2,3-dihydropyrimidin- 4(1H)-one 295.0 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.54 (br. s, 1 H), 7.44-7.52 (m, 1 H), 7.30 (d, J = 8.01 Hz, 1 H),7.25-7.27 (m, 2 H), 5.85 (s, 1 H), 4.71 (dt, J = 13.74, 5.38 Hz, 1 H),3.88 (td, J = 11.28, 5.38 Hz, 1 H), 3.80 (dt, J = 13.74, 5.95 Hz, 1 H),3.70 (td, J = 11.05, 5.15 Hz, 1 H), 2.49 (s, 3 H), 1.87 (t, J = 5.72 Hz,1 H) 25

1-(2- aminoethyl)-6- (4-fluoro-2- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 296.0 ¹H NMR (400 MHz,DMSO-d6) δ ppm 12.89 (s, 1 H), 7.80 (br. s., 3 H), 7.44 (dd, J = 8.39,6.64 Hz, 1 H), 7.18 (dd, J = 11.22, 2.24 Hz, 1 H), 6.97 (ddd, J = 8.40,8.40, 2.20 Hz, 1 H), 5.82 (s, 1 H), 4.54-4.66 (m, 1 H), 3.86 (s, 3 H),3.79-3.85 (m, 1 H), 2.88 (br. s, 2 H) 26

1-(2- aminoethyl)-6- (5-fluoro-2- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 296.2 1H NMR (400 MHz,DMSO-d6) δ ppm 12.91 (s, 1 H), 7.88 (br. s., 3 H), 7.42 (td, J = 8.78,3.12 Hz, 1 H), 7.34 (dd, J = 8.20, 3.12 Hz, 1 H), 7.23 (dd, J = 9.27,4.20 Hz, 1 H), 5.88 (d, J = 1.95 Hz, 1 H), 4.53-4.63 (m, 1 H), 3.85-3.93 (m, 1 H), 3.83 (s, 3 H), 2.85-2.99 (m, 2 H) 27

6-(4-fluoro-2- methoxyphenyl)- 1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 297.0 1H NMR (400 MHz, METHANOL-d4) δ ppm7.33 (dd, J = 8.39, 6.44 Hz, 1 H), 6.95 (dd, J = 10.83, 2.24 Hz, 1 H),6.82 (ddd, J = 8.40, 8.40, 2.30 Hz, 1 H), 5.73 (s, 1 H), 4.57- 4.69 (m,1 H), 3.87 (s, 3 H), 3.67-3.83 (m, 2 H), 3.55-3.62 (m, 1 H) 28

6-(5-fluoro-2- methoxyphenyl)- 1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 297.3 1H NMR (500 MHz, DMSO-d6) δ ppm 12.77(br. s., 1 H), 7.37 (ddd, J = 8.70, 8.70, 2.90 Hz, 1 H), 7.26 (dd, J =8.42, 3.05 Hz, 1 H), 7.18 (dd, J = 9.03, 4.15 Hz, 1 H), 5.82 (d, J =1.71 Hz, 1 H), 4.45-4.54 (m, 1 H), 3.82 (s, 3 H), 3.50-3.64 (m, 2 H),3.40- 3.47 (m, 1 H) 29

2-[6-(1H-indol-4- yl)-4-oxo-2- thioxo-3,4- dihydropyrimidin- 1(2H)-yl]acetamide 301.0 1H NMR (400 MHz, DMSO-d6) δ ppm 12.81 (br. s., 1 H),11.49 (br. s, 1 H), 7.54 (d, J = 8.31 Hz, 1 H), 7.49 (br. s., 1 H), 7.27(br. s., 1 H), 7.17 (t, J = 7.83 Hz, 1 H), 6.99 (d, J = 7.34 Hz, 1 H),6.96 (br. s., 1 H), 6.36 (br. s., 1 H), 5.84 (s, 1 H), 5.16-5.34 (m, 1H), 3.77-3.96 (m, 1 H) 30

1-(3- aminopropyl)-6- (1H-indol-4-yl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one trifluoroacetate 301.1 1H NMR (300 MHz, METHANOL-d4) δ ppm7.60 (d, J = 8.36 Hz, 1 H), 7.43 (d, J = 3.14 Hz, 1 H), 7.28 (t, J =7.66 Hz, 1 H), 7.12 (d, J = 6.97 Hz, 1 H), 6.37 (d, J = 2.09 Hz, 1 H),5.92 (s, 1 H), 4.49-4.63 (m, 1 H), 3.94-4.09 (m, 1 H), 2.63 (t, J = 7.84Hz, 2 H), 1.79-2.05 (m, 2 H) 31

2-[6-(1- benzofuran-7- yl)-4-oxo-2- thioxo-3,4- dihydropyrimidin- 1(2H)-yl]acetamide 301.9 1H NMR (300 MHz, METHANOL-d4) δ ppm 7.88 (d, J = 2.09Hz, 1 H), 7.80-7.84 (m, 1 H), 7.34-7.38 (m, 2 H), 6.99 (d, J = 2.26 Hz,1 H), 5.98 (s, 1 H) 32

1-(3- aminopropyl)-6- (1H-indazol-3- yl)-2-thioxo-2,3- dihydropyrimidin-4(1H)-one formate 302.1 1.36 min Waters Atlantis dC18 5um 4.6x50 mm, 95%H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95%MeCN to 5.0 min. (0.05% TFA). Flow rate: 2 mL/min 33

6-(1H-indol-3- yl)-1-(2- methoxyethyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 302.1 1H NMR (400 MHz, METHANOL-d3) δ ppm 7.63 (s, 1 H), 7.45(t, J = 8.01 Hz, 2 H), 7.22 (t, J = 7.79 Hz, 1 H), 7.16 (t, J = 7.33 Hz,1 H), 5.92 (s, 1 H), 4.64 (br. s., 2 H), 3.60 (t, J = 5.72 Hz, 2 H),3.03 (s, 3 H) 34

1-(3- aminopropyl)-6- (1-benzofuran- 7-yl)-2-thioxo- 2,3-dihydropyrimidin- 4(1H)-one hydrochloride 302.1 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.91 (d, J = 1.96 Hz, 1 H), 7.88 (dd, J = 6.85, 2.45Hz, 1 H), 7.41- 7.46 (m, 2 H), 7.03 (d, J = 1.96 Hz, 1 H), 5.98 (s, 1H), 4.48- 4.60 (m, 1 H), 3.87-4.00 (m, 1 H), 2.67 (t, J = 7.83 Hz, 2 H),1.83-1.98 (m, 2 H) 35

1-(2- methoxyethyl)- 6-(1H- pyrrolo[2,3- b]pyridin-3-yl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 303.1 1H NMR (400 MHz, DMSO-d6) δ ppm 12.30(br. s., 1 H), 8.30 (dd, J = 4.81, 1.60 Hz, 1 H), 7.94 (dd, J = 8.01,1.60 Hz, 1 H), 7.89 (s, 1 H), 7.17 (dd, J = 7.79, 4.58 Hz, 1 H), 5.87(s, 1 H), 4.44 (br. s., 2 H), 3.45 (t, J = 5.95 Hz, 2 H), 2.92 (s, 3 H)36

1-(2- aminoethyl)-6- (1-benzothien-3- yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 304.0 1H NMR (400 MHz, D2O) δppm 7.92-7.94 (m, 1H), 7.82 (s, 1H), 7.51-7.48 (m, 1H), 7.39- 7.37 (m,2H), 5.99 (s, 1H), 4.72- 4.71 (m, 1H), 4.05-3.99 (m, 1H), 3.01-2.94 (m,2H) 37

2-[6-(2,3- dihydro-1- benzofuran-5- yl)-4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]acetamide 304.0 1H NMR (300 MHz, DMSO-d6) δppm 12.74 (br. s., 1 H), 7.45 (br. s., 1 H), 7.29 (br. s, 1 H),7.09-7.17 (m, 2 H), 6.85 (d, J = 8.36 Hz, 1 H), 5.75 (s, 1 H), 4.59 (t,J = 8.62 Hz, 1 H), 3.20 (t, J = 8.88 Hz, 2 H) 38

1-(3- aminopropyl)-6- (2,3-dihydro-1- benzofuran-5- yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 304.1 1H NMR (300 MHz,DMSO-d6) δ ppm 12.74 (s, 1 H), 7.81 (br. s., 3 H), 7.37 (s, 1 H), 7.23(dd, J = 8.36, 2.09 Hz, 1 H), 6.88 (d, J = 8.36 Hz, 1 H), 5.76 (d, J =2.79 Hz, 1 H), 4.61 (t, J = 8.71 Hz, 2 H), 4.10 (t, J = 6.97 Hz, 2 H),3.25 (t, J = 8.71 Hz, 2 H), 2.53-2.61 (m, 2 H), 1.79-1.93 (m, 2 H) 39

6-(1-benzothien- 3-yl)-1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 305.0 1H NMR (400MHz, METHANOL-d4) 7.97 (d,1H), 7.92 (s, 1H), 7.61 (dd, 1H), 7.46-7.45 (m, 2H), 5.92 (s, 1H),4.65-4.63 (m, 1H), 3.90-3.85 (m, 1H), 3.84-3.80 (m, 1H), 3.62-3.61 (m,1H) 40

6-(1-benzothien- 2-yl)-1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 305.0 1H NMR (400 MHz, DMSO-d6) δ ppm 12.82(br. s., 1 H), 8.02- 8.06 (m, 1 H), 7.89-7.94 (m, 1 H), 7.74 (s, 1 H),7.41-7.47 (m, 2 H), 6.06 (d, J = 2.29 Hz, 1 H), 4.86 (t, J = 6.18 Hz, 1H), 4.31 (t, J = 6.18 Hz, 2 H), 3.63 (td, J = 6.40, 6.40 Hz, 2 H) 41

6-(2,3-dihydro- 1-benzofuran-7- yl)-1-(2- methyloxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 305.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.89 (br. s., 1 H), 7.31 (d, J = 7.33 Hz, 1 H), 7.03 (d, J = 7.56 Hz, 1H), 6.93 (t, J = 7.56 Hz, 1 H), 5.84 (s, 1 H), 4.68-4.81 (m, 1 H), 4.63(t, J = 8.70 Hz, 2 H), 3.95- 4.05 (m, 1 H), 3.67 (br. s., 1 H), 3.48(br. s, 1 H), 3.28 (t, J = 8.70 Hz, 2 H), 3.14 (s, 3 H) 42

6-(1,3- benzothiazol-7- yl)-1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 305.9 1H NMR (400 MHz, DMSO-d6) δ ppm 12.91(s, 1 H) 9.50 (s, 1 H) 8.24 (d, J = 7.34 Hz, 1 H) 7.71 (dd, J = 7.83,7.34 Hz, 1 H) 7.65 (d, J = 7.83 Hz, 1 H) 6.03 (s, 1 H) 4.72 (t, J = 5.62Hz, 1 H) 4.22-4.31 (m, 1 H) 3.86-3.96 (m, 1 H) 3.43-3.56 (m, 2 H) 43

1-(3- aminopropyl)-6- (2-methoxy-5- methylphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 306.1 ¹H NMR (500 MHz,DMSO-d6) δ ppm 12.79 (s, 1 H), 7.92 (br. s., 3 H), 7.34 (dd, J = 8.29,1.22 Hz, 1 H), 7.19 (d, J = 1.46 Hz, 1 H), 7.08 (d, J = 8.54 Hz, 1 H),5.78 (d, J = 1.46 Hz, 1 H), 4.38 (br. s., 1 H), 3.62 (br. s., 1 H), 3.34(s, 3 H), 2.47-2.56 (m, 2 H), 2.30 (s, 3 H), 1.84 (s, 1 H), 1.69-1.79(m, 1 H) 44

2-[6-(2- methoxy-5- methylpyridin-3- yl)-4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]acetamide 306.7 1H NMR (400 MHz, DMSO-d6): δ12.82 (br. s., 1H), 8.14 (s, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 7.31 (s,1H), 7.02 (s, 1H), 5.86 (s, 1H), 5.50 (br. s., 1H), 3.87 (s, 4H), 2.20(s, 3H). 45

1-(3- aminopropyl)-6- (2-methoxy-5- methylpyridin-3- yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one trifluoroacetate 306.9 1H NMR (400 MHz,DMSO-d6): δ 12.82 (s, 1H), 8.20 (s, 1H), 7.71 (s, 1H), 7.60 (br. s.,2H), 5.90 (s, 1H), 4.35-4.45 (m, 1H), 3.97 (s, 3H), 3.58-3.65 (m, 1H),2.50-2.65 (m, 2H), 2.30 (s, 3H), 1.90-1.65 (m, 2H). 46

6-[2-(2- hydroxyethyl) phenyl]-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 307.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.44 (br. s., 1 H), 7.44-7.52 (m, 1 H), 7.41 (d, J = 7.10 Hz, 1 H), 7.34(dd, J = 7.79, 6.87 Hz, 1 H), 7.23-7.25 (m, 1 H), 5.84 (s, 1 H), 4.48(dt, J = 13.68, 5.07 Hz, 1 H), 3.81-3.99 (m, 3 H), 3.65 (ddd, J = 10.25,6.93, 5.27 Hz, 1 H), 3.58 (dt, J = 10.36, 5.24 Hz, 1 H), 3.16 (s, 3 H),2.83 (dt, J = 14.25, 6.96 Hz, 1 H), 2.72 (dt, J = 14.20, 7.00 Hz, 1 H)47

6-(2,3-dihydro- 1,4- benzodioxin-5- yl)-1-(2- hydroxyethyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 307.1 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 9.57 (br. s, 1 H), 7.02 (dd, J = 8.24, 1.37 Hz, 1H), 6.94 (dd, J = 7.90, 7.90 Hz, 1 H), 6.80 (dd, J = 7.56, 1.37 Hz, 1H), 5.87 (s, 1 H), 4.73 (dt, J = 14.14, 5.52 Hz, 1 H), 4.30 (s, 4 H),3.97 (dt, J = 14.31, 5.78 Hz, 1 H), 3.83- 3.92 (m, 1 H), 3.67-3.78 (m, 1H) 48

1-(2- aminoethyl)-6- (3,5- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 308.0 3.442 min Column:XBRIDGE- C18 4.6X75 mm 3.5 μm, Mobile phase-A = 0.1% TFA IN ACN, B =0.1% TFA IN WATER; Time(min)/% B = 0/90, 0.8/90, 1.8/55, 3/5, 6.5/5,7/90; Flow: 0.8 mL/min, Column Temp = 40° C.; Diluent: CAN 49

1-(2- methoxyethyl)- 6-(3-methoxy-6- methylpyridin-2- yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 308.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.41 (br. s., 1 H), 7.25-7.27 (m, 2 H), 5.90 (s, 1 H), 4.22-4.38 (m, 2H), 3.84 (s, 3 H), 3.57 (t, J = 6.41 Hz, 2 H), 3.15 (s, 3 H), 2.53 (s, 3H) 50

1-(2- methoxyethyl)- 6-(2-methoxy-6- methylpyridin-3- yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 308.1 1H NMR (400 MHz, METHANOL-d3) δ ppm7.56 (d, J = 7.56 Hz, 1 H), 6.94 (d, J = 7.33 Hz, 1 H), 5.74 (s, 1 H),4.72 (dt, J = 13.57, 3.86 Hz, 1 H), 3.95 (s, 3 H), 3.67-3.83 (m, 2 H),3.35-3.43 (m, 1 H), 3.11 (s, 3 H), 2.49 (s, 3 H) 51

1-(2- methoxyethyl)- 6-(2-methoxy-5- methylpyridin-3- yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 308.1 1H NMR (400 MHz, METHANOL-d3) δppm8.11 (s, 1 H), 7.56 (d, J = 2.06 Hz, 1 H), 5.76 (s, 1 H), 4.64-4.76 (m,1 H), 3.94 (s, 3 H), 3.68-3.82 (m, 2 H), 3.35-3.44 (m, 1 H), 3.10 (s, 3H), 2.30 (s, 3 H) 52

6-[2-(2- aminoethoxy) phenyl]-1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one formate 308.2 2.14 min Waters Atlantis dC185um 4.6x50 mm, 95% H2O/5% MeCN linear to 5%/H2O/95% MeCN over 4.0 min,HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05% TFA). Flow rate: 2 mL/min 53

1-(2- aminoethyl)-6- [2-(2- hydroxyethoxy) phenyl]-2-thioxo- 2,3-dihydropyrimidin- 4(1H)-one hydrochloride 308.2 1H NMR (400 MHz, CD3OD)δ 3.09 (ddd, J = 12.9, 7.6, 6.1 Hz, 1 H), 3.19 (ddd, J = 12.9, 7.6, 6.5Hz, 1 H), 3.81-3.91 (m, 2 H), 4.16 (ddd, J = 10.6, 4.7, 3.5 Hz, 1 H),4.22 (ddd, J = 10.8, 6.1, 3.9 Hz, 1 H), 4.26-4.37 (m, 1 H), 4.60-4.74(m, 1 H), 5.84 (s, 1 H), 7.15 (td, J = 7.5, 1.0 Hz, 1 H), 7.23 (dd, J =8.4, 0.6 Hz, 1 H), 7.36 (dd, J = 7.4, 1.6 Hz, 1 H), 7.57 (ddd, J = 8.5,7.5, 1.8 Hz, 1 H) 54

6-(3,5- dimethoxyphenyl)- 1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 309.1 1H NMR (300 MHz, DMSO-d6) δ ppm 12.72(br. s, 1 H), 6.67 (d, J = 2.26 Hz, 2 H), 6.62 (t, J = 2.30 Hz, 1 H),5.76 (d, J = 2.26 Hz, 1 H), 4.77 (t, J = 5.57 Hz, 1 H), 4.14 (t, J =6.45 Hz, 2 H), 3.78 (s, 6 H), 3.57 (td, J = 5.90 Hz, 2 H) 55

1-(2- methoxyethyl)- 6-[2- (methylthio)phen- yl]-2-thioxo- 2,3-dihydropyrimidin- 4(1H)-one 309.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.66 (br. s, 1 H), 7.40-7.50 (m, 1 H), 7.28 (d, J = 8.01 Hz, 1 H), 7.24(d, J = 6.64 Hz, 2 H), 5.82 (s, 1 H), 4.59-4.71 (m, 1 H), 3.68-3.81 (m,2 H), 3.41-3.51 (m, 1 H), 3.15 (s, 3 H), 2.48 (s, 3 H) 56

2-[6-(4-fluoro-2- methoxyphenyl)- 4-oxo-2-thioxo- 3,4- dihydropyrimidin-1(2H)- yl]acetamide 310.0 1H NMR (400 MHz, DMSO-d6) δ ppm 12.78 (s, 1H), 7.27 (br. s., 1 H), 7.17 (dd, J = 8.30, 6.93 Hz, 1 H), 7.08 (dd, J =11.13, 2.15 Hz, 1 H), 6.97 (br. s., 1 H), 6.86 (td, J = 8.44, 2.24 Hz, 1H), 5.78 (d, J = 2.15 Hz, 1 H), 5.36 (br. s., 2 H), 3.28 (s, 3 H) 57

1-(3- aminopropyl)-6- (4-fluoro-2- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 310.0 1H NMR (400 MHz,METHANOL-d4) δppm 7.36 (dd, J = 8.39, 6.44 Hz, 1 H), 7.01 (dd, J =10.83, 2.24 Hz, 1 H), 6.85 (td, J = 8.30, 2.34 Hz, 1 H), 5.79 (s, 1 H),4.51-4.63 (m, 1 H), 3.89 (s, 3 H), 3.69-3.81 (m, 1 H), 2.76 (t, J = 7.81Hz, 2 H), 1.93-2.07 (m, 1 H), 1.74-1.88 (m, 1 H) 58

1-(3- aminopropyl)-6- (5-fluoro-2- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 310.0 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.31 (td, J = 8.59, 3.12 Hz, 1 H), 7.14- 7.23 (m, 2H), 5.81 (s, 1 H), 4.51-4.64 (m, 1 H), 3.87 (s, 3 H), 3.73-3.83 (m, 1H), 2.77 (t, J = 7.71 Hz, 2 H), 1.95-2.09 (m, 1 H), 1.77-1.91 (m, 1 H)59

2-[6-(5-fluoro-2- methoxyphenyl)- 4-oxo-2-thioxo- 3,4- dihydropyrimidin-1(2H)- yl]acetamide 310.0 1H NMR (500 MHz, DMSO-d6) δ ppm 3.35 (br. s.,2 H) 3.83 (s, 3 H) 5.85-5.90 (m, 1 H) 7.03 (d, J = 7.56 Hz, 1 H) 7.07(br. s., 1 H) 7.19 (dd, J = 9.15, 4.27 Hz, 1 H) 7.33 (br. s., 1 H) 7.38(td, J = 8.72, 3.05 Hz, 1 H) 12.85 (br. s., 1 H) 60

6-(2-fluoro-6- methoxyphenyl)- 1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 311.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm10.08 (br. s., 1 H), 7.44 (ddd, J = 8.30, 8.30, 6.80 Hz, 1 H), 6.82 (t,J = 8.47 Hz, 1 H), 6.77 (d, J = 8.47 Hz, 1 H), 5.88 (s, 1 H), 4.49-4.65(m, 1 H), 3.88- 3.97 (m, 1 H), 3.85 (s, 3 H), 3.56-3.66 (m, 1 H),3.45-3.54 (m, 1 H), 3.16 (s, 3 H) 61

1-(2- aminoethyl)-6- (2-chloro-4- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 311.9 1H NMR (300 MHz,DMSO-d6) δ ppm 12.99 (br. s., 1 H), 7.74 (br. s., 3 H), 7.55 (d, J =8.36 Hz, 1 H), 7.30 (d, J = 2.09 Hz, 1 H), 7.12 (dd, J = 8.36, 2.09 Hz,1 H), 5.91 (d, J = 2.09 Hz, 1 H), 4.53- 4.71 (m, 1 H), 3.85 (s, 3 H),3.73-3.84 (m, 1 H), 2.92-3.08 (m, 1 H), 2.77-2.90 (m, 1 H) 62

1-(2- aminoethyl)-6- (4-chloro-2- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 312.0 1H NMR (400 MHz,METHANOL-d3) δ ppm 7.34 (d, J = 8.24 Hz, 1 H), 7.27 (d, J = 1.60 Hz, 1H), 7.16 (dd, J = 8.13, 1.72 Hz, 1 H), 5.83 (s, 1 H), 4.68-4.81 (m, 1H), 4.01- 4.12 (m, 1 H), 3.91 (s, 3 H), 2.97-3.16 (m, 2 H) 63

1-(2- aminoethyl)-6- (5-chloro-2- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 312.2 1.67 min Waters AtlantisdC18 5um 4.6x50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05% TFA). Flow rate: 2mL/min 64

6-(5-chloro-2- methoxyphenyl)- 1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 313.2 1H NMR (500 MHz, DMSO-d6) δ ppm 12.76(br. s., 1 H) 7.57 (dd, J = 8.78, 2.68 Hz, 1 H) 7.42 (d, J = 2.68 Hz, 1H) 7.19 (d, J = 9.03 Hz, 1 H) 5.83 (d, J = 2.20 Hz, 1 H) 5.18 (br. s., 1H) 4.44- 4.52 (m, 1 H) 3.83 (s, 3 H) 3.56- 3.62 (m, 1 H) 3.53 (dt, J =13.66, 6.83 Hz, 1 H) 3.42 (ddd, J = 10.12, 6.46, 3.90 Hz, 1 H) 65

6-(5-chloro-2- methoxypyridin- 3-yl)-1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 314.0 1H NMR (400 MHz, DMSO-d6) δ ppm 12.80(br. s., 1 H), 8.38 (d, J = 2.75 Hz, 1 H), 7.89 (d, J = 2.75 Hz, 1 H),5.93 (d, J = 2.06 Hz, 1 H), 4.45-4.54 (m, 1 H), 3.89 (s, 3 H), 3.55-3.65(m, 1 H), 3.36-3.51 (m, 2 H) 66

1-(2- methoxyethyl)- 6-(1-methyl-1H- indol-2-yl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 316.0 1H NMR (400 MHz, CHLOROFORM-d) d ppm9.90 (br. s, 1 H), 7.67 (d, J = 7.79 Hz, 1 H), 7.31-7.42 (m, 2 H), 7.21(dd, J = 7.10, 7.10 Hz, 1 H), 6.65 (s, 1 H), 5.98 (s, 1H, 4.71 (br. s, 1H), 4.34 (br. s, 1 H), 3.72- 3.84 (m, 1 H), 3.69 (s, 3 H), 3.43-3.58 (m,1 H), 3.11 (s, 3 H) 67

1-(2- methoxyethyl)- 6-(1-methyl-1H- indol-3-yl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 316.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.70 (br. s., 1 H), 7.50 (d, J = 7.79 Hz, 1 H), 7.36-7.43 (m, 2 H), 7.33(t, J = 7.44 Hz, 1 H), 7.19-7.26 (m, 1 H), 5.99 (s, 1 H), 4.61 (br. s.,2 H), 3.88 (s, 3 H), 3.68 (t, J = 5.50 Hz, 2 H), 3.18 (s, 3 H) 68

2-[6-(1- benzothien-3- yl)-4-oxo-2- thioxo-3,4- dihydropyrimidin- 1(2H)-yl]acetamide 318.0 1H NMR (400 MHz, METHANOL-d3) δppm 7.99- 8.12 (m, 1H), 7.92 (s, 1 H), 7.77 (d, J = 6.18 Hz, 1 H), 7.42- 7.57 (m, 2 H), 6.02(s, 1 H), 5.17-5.68 (m, 1 H), 3.77-4.25 (m, 1 H) 69

2-[6-(1- benzothien-2- yl)-4-oxo-2- thioxo-3,4- dihydropyrimidin- 1(2H)-yl]acetamide 318.0 1H NMR (400 MHz, DMSO-d6) δ ppm 12.63 (br. s, 1 H),7.97- 8.04 (m, 1 H), 7.86-7.93 (m, 1 H), 7.61 (s, 1 H), 7.40-7.48 (m, 2H), 7.34 (br. s, 1 H), 6.97 (br. s., 1 H), 6.03-6.11 (m, 1 H), 4.53-5.06(m, 2 H) 70

3-methoxy-4-[3- (2- methoxyethyl)- 6-oxo-2-thioxo- 1,2,3,6-tetrahydropyrimi- din-4- yl]benzonitrile 318.1 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 9.46 (br. s, 1 H), 7.32-7.42 (m, 2 H), 7.20 (s, 1H), 5.75 (s, 1 H), 4.71 (dt, J = 14.20, 3.43 Hz, 1 H), 3.90 (s, 3 H),3.80 (td, J = 9.79, 3.78 Hz, 1 H), 3.64 (ddd, J = 14.20, 9.39, 4.35 Hz,1 H), 3.36 (ddd, J = 10.30, 4.35, 3.21 Hz, 1 H), 3.14 (s, 3 H) 71

1-(3- aminopropyl)-6- (1-benzothien-2- yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 318.1 1H NMR (300 MHz,DMSO-d6) δ ppm 12.90 (br. s., 1 H), 8.06- 8.11 (m, 1 H), 7.95-8.01 (m, 1H), 7.80 (s, 1 H), 7.73 (br. s., 3 H), 7.47-7.54 (m, 2 H), 6.16 (s, 1H), 4.22-4.33 (m, 2 H), 2.60- 2.70 (m, 2 H), 1.94-2.06 (m, 2 H) 72

1-(3- aminopropyl)-6- (1,3- benzothiazol-7- yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one trifluoroacetate 319.2 1H NMR (400 MHz,DMSO-d6) δ ppm 12.98 (s, 1 H), 9.54 (s, 1 H), 8.29 (d, J = 7.34 Hz, 1H), 7.72 (m, J = 9.78 Hz, 2 H), 7.52 (br. s., 3 H), 6.10 (d, J = 1.96Hz, 1 H), 4.21-4.31 (m, 1 H), 3.49- 3.82 (m, 3 H), 1.68-1.87 (m, 2 H) 73

6-(1-benzothien- 7-yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 319.4 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.72 (br. s, 1 H), 7.94 (dd, J = 8.01, 0.69 Hz, 1 H), 7.53 (d, J = 5.50Hz, 1 H), 7.49 (t, J = 7.67 Hz, 1 H), 7.42 (d, J = 5.50 Hz, 1 H), 7.33(d, J = 7.33 Hz, 1 H), 6.02 (s, 1 H), 4.55 (dt, J = 14.03, 4.89 Hz, 1H), 4.06 (dt, J = 13.40, 6.58 Hz, 1 H), 3.65 (ddd, J = 10.42, 6.98, 5.04Hz, 1 H), 3.47 (dt, J = 10.42, 5.09 Hz, 1 H), 3.07 (s, 3 H) 74

6-(1-benzothien- 4-yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 319.4 1H NMR (301 MHz, DMSO-d6) δ ppm 12.85(br. s., 1 H), 8.16 (t, J = 4.48 Hz, 1 H), 7.90 (d, J = 5.51 Hz, 1 H),7.47 (d, J = 4.36 Hz, 2 H), 7.37 (d, J = 5.51 Hz, 1 H), 5.87 (s, 1 H),4.31 (ddd, J = 13.31, 7.57, 5.74 Hz, 1 H), 3.84 (dt, J = 13.37, 6.74 Hz,1 H), 3.32-3.45 (m, 2 H), 2.82 (s, 3 H) 75

6-(1,3- benzothiazol-2- yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 320.0 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.91 (br. s., 1 H), 8.14 (d, J = 8.01 Hz, 1 H), 7.98 (d, J = 7.79 Hz, 1H), 7.61 (ddd, J = 8.01, 7.10, 1.15 Hz, 1 H), 7.54 (ddd, J = 7.80, 7.80,0.90 Hz, 1 H), 6.27 (s, 1 H), 5.04 (t, J = 5.27 Hz, 2 H), 3.63 (t, J =5.27 Hz, 2 H), 3.09 (s, 3 H) 76

1-(3- aminopropyl)-6- (2,3-dihydro- 1,4- benzodioxin-6-yl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one hydrochloride 320.0 1H NMR(300 MHz, DMSO-d6) δ ppm 12.76 (br. s., 1 H), 7.71 (br. s., 3 H), 7.07(s, 1 H), 6.93- 7.02 (m, 2 H), 5.77 (d, J = 2.09 Hz, 1 H), 4.30 (s, 4H), 4.03- 4.18 (m, 2 H), 2.53-2.66 (m, 2 H), 1.76-1.93 (m, 2 H) 77

2-{2-[6-(2- methoxyphenyl)- 4-oxo-2-thioxo- 3,4- dihydropyrimidin-1(2H)- yl]ethyl}guanidine hydrochloride 320.0 1H NMR (500 MHz, DMSO-d6)δ ppm 12.85 (s, 1 H), 7.65 (br. t, J = 6.10, 6.10 Hz, 1 H), 7.53 (td, J= 7.93, 1.46 Hz, 1 H), 7.32 (dd, J = 7.56, 1.46 Hz, 1 H), 7.17 (d, J =8.29 Hz, 1 H), 7.07 (t, J = 7.44 Hz, 2 H), 6.97 (br. s., 4 H), 5.80 (d,J = 2.20 Hz, 1 H), 4.54 (br. d, J = 13.70 Hz, 1 H), 3.84 (s, 3 H), 3.63(m, J = 9.03 Hz, 1 H), 3.53 (td, J = 9.33, 4.51 Hz, 1 H), 3.17-3.22 (m,1 H) 78

6-(1,3- benzothiazol-7- yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 320.4 1H NMR (301 MHz, CHLOROFORM-d) δ ppm9.97 (br. s., 1 H), 9.10 (s, 1 H), 8.27 (d, J = 8.26 Hz, 1 H), 7.66 (t,J = 7.80 Hz, 1 H), 7.44 (d, J = 7.34 Hz, 1 H), 6.01 (s, 1 H), 4.48 (dt,J = 14.00, 4.82 Hz, 1 H), 4.11-4.32 (m, 1 H), 3.45- 3.69 (m, 2 H), 3.06(s, 3 H) 79

1-(2- aminoethyl)-6- [2-(3- aminopropoxy) phenyl]-2-thioxo- 2,3-dihydropyrimidin- 4(1H)-one hydrochloride 321.0 1H NMR (400 MHz,METHANOL-d4) δppm 7.57 (t, J = 7.42 Hz, 1 H), 7.40 (d, J = 6.83 Hz, 1H), 7.22 (d, J = 8.59 Hz, 1 H), 7.15 (t, J = 7.03 Hz, 1 H), 5.83 (s, 1H), 4.90- 5.00 (m, 1 H), 4.26-4.35 (m, 1 H), 4.17-4.25 (m, 1 H), 4.02-4.13 (m, 1 H), 2.97-3.18 (m, 4 H), 2.08-2.20 (m, 2 H) 80

6-(2,3-dihydro- 1,4- benzodioxin-5- yl)-1-(2- methoxyethyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 321.2 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 9.79 (br. s., 1 H), 7.00 (dd, J = 8.24, 1.60 Hz, 1H), 6.92 (t, J = 7.90 Hz, 1 H), 6.79 (dd, J = 7.56, 1.60 Hz, 1 H), 5.84(s, 1 H), 4.70 (dt, J = 13.91, 4.84 Hz, 1 H), 4.29 (s, 4 H), 3.94 (dt, J= 14.08, 6.93 Hz, 1 H), 3.70 (ddd, J = 10.19, 7.67, 5.95 Hz, 1 H), 3.48(ddd, J = 10.25, 6.13, 4.24 Hz, 1 H), 3.16 (s, 3 H) 81

1-(2- aminoethyl)-6- (2,4-dimethoxy- 5- methylphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 321.8 1H NMR (400 MHz,DMSO-d6): δ 12.85 (s, 1 H), 7.80 (br. s., 3 H), 7.11 (s, 1 H), 6.76 (s,1 H), 5.75 (s, 1 H), 4.58-4.69 (m, 1 H), 3.88-3.95 (m, 1H), 3.89 (s, 4H), 3.86 (s, 3 H), 2.82-2.95 (m, 2 H), 2.10 (s, 3 H): 82

1-(3- aminopropyl)-6- (3,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 322.0 1H NMR (400 MHz,DMSO-d6) δ ppm 12.76 (br. s., 1 H), 7.71 (br. s., 3 H), 7.13 (d, J =1.96 Hz, 1 H), 7.05 (d, J = 5.38 Hz, 2 H), 5.81 (d, J = 1.96 Hz, 1 H),4.09- 4.20 (m, 2 H), 3.82 (s, 3 H), 3.80 (s, 3 H), 2.53-2.62 (m, 2 H),1.79-1.90 (m, 2 H) 83

2-[6-(3,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]acetamide 322.0 1H NMR (300 MHz, DMSO-d6) δ ppm 12.75 (br. s.,1 H), 7.46 (br. s., 1 H), 7.16 (br. s., 1 H), 7.00-7.09 (m, 2 H),6.91-6.99 (m, 1 H), 5.81 (s, 1 H), 4.98- 5.44 (m, 1 H), 3.94-4.29 (m, 1H), 3.80 (s, 3 H), 3.74 (s, 3 H) 84

1-(2- aminoethyl)-6- (2,5-dimethoxy- 4- methylphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 322.0 1H NMR (400 MHz,METHANOL-d4): δ 6.95 (s, 1H), 6.81 (s, 1H), 5.75 (s, 1H), 4.58-4.47 (m,1H), 4.11-4.20 (m, 1H), 3.75 (s, 3H), 3.30 (s, 3H), 2.95-3.08 (m, 2H),2.18 (s, 3H). 85

1-(3- aminopropyl)-6- (3,5- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 322.0 3.567 min (Column:XBRIDGE- C18 4.6X75 mm 3.5 μm; Mobile phase-A = 0.1% TFA IN ACN, B =0.1% TFA IN WATER; Time(min)/% B = 0/90, 0.8/90, 1.8/55, 3/5, 6.5/5,7/90 Flow: 0.8 mL/min, Column Temp = 40° C.; Diluent: CAN) 86

2-[6-(3,5- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]acetamide 322.1 1H NMR (300 MHz, DMSO-d6) δ ppm 12.79 (br. s.,1 H), 7.46 (br. s., 1 H), 7.17 (br. s., 1 H), 6.62 (d, J = 1.74 Hz, 1H), 6.60 (s, 2 H), 5.83 (d, J = 1.92 Hz, 1 H), 5.17 (br. s, 1 H), 4.08(br. s, 1 H), 3.75 (s, 6 H) 87

1-(3- aminopropyl)-6- (2,5- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 322.1 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.08- 7.12 (m, 2 H), 6.93 (s, 1 H), 5.79 (s, 1 H),4.47-4.62 (m, 1 H), 3.84-3.87 (m, 1 H), 3.83 (s, 3 H), 3.78 (s, 3 H),2.76 (t, J = 7.71 Hz, 2 H), 1.95-2.09 (m, 1 H), 1.78-1.93 (m, 1 H) 88

1-(3- aminopropyl)-6- [2-(2- hydroxyethoxy) phenyl]-2-thioxo- 2,3-dihydropyrimidin- 4(1H)-one hydrochloride 322.2 1H NMR (500 MHz, CD₃OD)δ 1.81-1.92 (m, 1 H), 2.05 (dqd, J = 13.4, 8.1, 5.6 Hz, 1 H), 2.76 (t, J= 7.8 Hz, 2 H), 3.82-3.90 (m, 2 H), 3.90-4.02 (m, 1 H), 4.16 (ddd, J =11.0, 4.6, 3.7 Hz, 1 H), 4.20 (ddd, J = 10.7, 5.9, 4.1 Hz, 1 H),4.45-4.59 (m, 1 H), 5.82 (s, 1 H), 7.13 (t, J = 7.4 Hz, 1 H), 7.21 (d, J= 8.5 Hz, 1 H), 7.35 (dd, J = 7.4, 1.6 Hz, 1 H), 7.55 (ddd, J = 8.4,7.6, 1.3 Hz, 1 H) 89

[6-(2, 4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]acetic acid 323.1 2.09 min Waters Atlantis dC18 5um 4.6x50 mm,95%/H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95% MeCN to 5.0 min. (0.05% TFA). Flow rate: 2 mL/min 90

1-(2- aminoethyl)-6- (5-fluoro-2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 325.9 1H NMR (400 MHz,DMSO-d6): δ 12.88 (s, 1 H), 7.87 (br. s., 3 H), 7.32 (d, 1 H), 6.97 (d,1 H), 5.82 (s, 1 H), 4.55-4.66 (m, 1 H), 3.95 (s, 3 H), 3.87 (s, 3 H),3.83-3.92 (m, 1H), 2.87-2.98 (m, 2 H). 91

1-(3- aminopropyl)-6- (2-chloro-4- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 326.0 1H NMR (400 MHz,DMSO-d6) δ ppm 12.88 (s, 1 H), 7.66 (br. s, 3 H), 7.55 (d, J = 8.80 Hz,1 H), 7.27 (d, J = 2.45 Hz, 1 H), 7.09 (dd, J = 8.80, 2.45 Hz, 1 H),5.89 (d, J = 1.96 Hz, 1 H), 4.36- 4.46 (m, 1 H), 3.85 (s, 3 H),3.57-3.63 (m, 1 H), 2.53-2.64 (m, 2 H), 1.86-1.95 (m, 1 H), 1.67-1.76(m, 1 H) 92

1-(3- aminopropyl)-6- (5-chloro-2- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 326.3 ¹H NMR (500 MHz,METHANOL-d4) δ ppm 7.57 (dd, J = 9.03, 2.68 Hz, 1 H), 7.44 (d, J = 2.44Hz, 1 H), 7.19 (d, J = 9.03 Hz, 1 H), 5.83 (s, 1 H), 4.53-4.63 (m, 1 H),3.91 (s, 3 H), 3.75-3.84 (m, 1 H), 2.80 (t, J = 7.81 Hz, 2 H), 1.98-2.08(m, 1 H), 1.80-1.90 (m, 1 H) 93

1-(3- aminopropyl)-6- (5-chloro-2- methoxypyridin- 3-yl)-2-thioxo- 2,3-dihydropyrimidin- 4(1H)-one hydrochloride 326.9 1H NMR (400 MHz,METHANOL-d4) δ ppm 8.37 (d, J = 2.45 Hz, 1 H), 7.92 (d, J = 2.45 Hz, 1H), 5.90 (s, 1 H), 4.52-4.62 (m, 1 H), 4.02 (s, 3 H), 3.74-3.85 (m, 1H), 2.84 (t, J = 7.83 Hz, 2 H), 1.98-2.09 (m, 1 H), 1.81-1.94 (m, 1 H)94

6-(5-chloro-2- methoxyphenyl)- 1-(3- hydroxypropyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 327.0 1H NMR (400 MHz, METHANOL-d3) δ ppm7.51 (dd, J = 8.93, 2.52 Hz, 1 H), 7.39 (d, J = 2.29 Hz, 1 H), 7.14 (d,J = 8.93 Hz, 1 H), 5.77 (s, 1 H), 4.52 (ddd, J = 13.91, 9.79, 4.69 Hz, 1H), 3.88 (s, 3 H), 3.78 (ddd, J = 14.43, 10.08, 5.27 Hz, 1 H), 3.36 (t,J = 6.18 Hz, 2 H), 1.82-1.96 (m, 1 H), 1.62-1.76 (m, 1 H) 95

1-(2- aminoethyl)-6- (3-methoxy-2- naphthyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 327.9 1H NMR (400 MHz,DMSO-d6) δ ppm 12.92 (d, J = 1.83 Hz, 1 H), 7.97 (s, 1 H), 7.90 (t, J =7.33 Hz, 2 H), 7.73 (br. s., 3 H), 7.53- 7.59 (m, 2 H), 7.40-7.46 (m, 1H), 5.92 (d, J = 2.29 Hz, 1 H), 4.58-4.69 (m, 1 H), 3.92 (s, 3 H),3.77-3.87 (m, 1 H), 2.79- 2.99 (m, 2 H) 96

6-(5-chloro-2- methoxypyridin- 3-yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 328.0 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.79 (br. s., 1 H), 8.24 (d, J = 2.52 Hz, 1 H), 7.54 (d, J = 2.52 Hz, 1H), 5.78 (d, J = 2.29 Hz, 1 H), 4.76 (dt, J = 14.37, 2.89 Hz, 1 H), 3.96(s, 3 H), 3.86 (td, J = 9.96, 3.43 Hz, 1 H), 3.65 (ddd, J = 14.20, 9.85,3.89 Hz, 1 H), 3.36 (dt, J = 10.36, 3.52 Hz, 1 H), 3.17 (s, 3 H) 97

1-(2- aminoethyl)-6- (2- methoxyquinolin- 3-yl)-2-thioxo- 2,3-dihydropyrimidin- 4(1H)-one trifluoroacetate 328.8 1H NMR (400 MHz,DMSO-d6): δ 12.92 (br. s., 1 H), 8.20 (s, 1 H), 7.83-7.65 (m, 6 H), 7.38(t, 1 H), 6.01 (s, 1 H), 4.52-4.61 (m, 1 H), 3.70-3.80 (m, 1H), 3.68 (s,3 H), 2.98-3.18 (m, 2 H). 98

1-(3- aminopropyl)-2- thioxo-6-[2-(2H- 1,2,3-triazol-2- yl)phenyl]-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 328.9 0.893 min Column: LCMS-QSupelco 3x30 mm; Mobile phase: from 0% CH3CN (0.1% TFA) in water (0.1%TFA) to 60% CH3CN (0.1% TFA) in water (0.1% TFA) 99

2-{4-oxo-2- thioxo-6-[2-(2H- 1,2,3-triazol-2- yl)phenyl]-3,4-dihydropyrimidin- 1(2H)- yl}acetamide 329.0 1H NMR (400 MHz, DMSO-d6): δ12.76 (s, 1H), 8.11 (s, 2H), 7.98 (d, 1H), 7.72 (t, 1H), 7.55 (t, 1H),7.45 (d, 1H), 7.35 (s, 1H), 7.04 (s, 1H), 5.68 (s, 1H), 5.22 (d, 1H),3.79 (d, 1H).: 100

1-(2- hydroxyethyl)-6- (3-methoxy-2- naphthyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 329.4 1H NMR (400 MHz, DMSO-d6) δ ppm 12.80(d, J = 1.37 Hz, 1 H), 7.92 (s, 1 H), 7.88 (d, J = 9.16 Hz, 2 H), 7.54(ddd, J = 8.13, 6.98, 0.92 Hz, 1 H), 7.49 (s, 1 H), 7.41 (ddd, J = 8.24,6.87, 0.92 Hz, 1 H), 5.87 (d, J = 2.29 Hz, 1 H), 4.68 (br. s., 1 H),4.47-4.58 (m, 1 H), 3.91 (s, 3 H), 3.44-3.54 (m, 2 H) 101

1-(2- methoxyethyl)- 2-thioxo-6-[2- (2H-1,2,3- triazol-2-yl)phenyl]-2,3- dihydropyrimidin- 4(1H)-one 330.1 1H NMR (300 MHz,DMSO-d6) δ ppm 12.77 (br. s., 1 H), 8.14 (s, 2 H), 8.05 (d, J = 7.67 Hz,1 H), 7.77 (td, J = 7.67, 2.09 Hz, 1 H), 7.60-7.71 (m, 2 H), 5.79 (s, 1H), 4.32-4.44 (m, 1 H), 3.47- 3.62 (m, 1 H), 3.36-3.46 (m, 1 H), 2.99(s, 3 H) 102

6-(2- ethoxyphenyl)- 1- (tetrahydrofuran- 2-ylmethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 333.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm10.25-10.39 (m, 1 H) 7.39- 7.50 (m, 1 H) 7.30-7.36 (m, 1 H) 7.00-7.07(m, 1 H) 6.88- 6.99 (m, 1 H) 5.81-5.88 (m, 1 H) 4.68-4.77 (m, 1 H) 4.56-4.65 (m, 1 H) 4.05-4.14 (m, 2 H) 3.49-3.57 (m, 1 H) 3.34- 3.44 (m, 1 H)3.05-3.13 (m, 1 H) 1.90-2.01 (m, 1 H)1.63- 1.78 (m, 1 H) 1.40-1.49 (m, 1H) 1.32-1.38 (m, 3 H) 1.23- 1.32 (m, 1 H) 103

2-{3-[6-(2- methoxyphenyl)- 4-oxo-2-thioxo- 3,4- dihydropyrimidin-1(2H)- yl]propyl}guanidine 334.1 1.31 min Waters Atlantis dC18 5um4.6x50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLDat 5% H2O/95% MeCN to 5.0 min. (0.05% TFA). Flow rate: 2 mL/min 104

6-(2- ethoxyphenyl)- 1-(2- isopropoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 335.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm10.15 (br. s., 1 H) 7.45 (ddd, J = 8.29, 7.51, 1.76 Hz, 1 H) 7.24 (dd, J= 7.51, 1.66 Hz, 1 H) 7.03 (ddd, J = 7.41, 0.78 Hz, 1 H) 6.94 (d, J =8.39 Hz, 1 H) 5.83 (d, J = 2.34 Hz, 1 H) 4.69 (ddd, J = 13.46, 5.66,4.10 Hz, 1 H) 4.10 (q, J = 6.89 Hz, 2 H) 3.68-3.85 (m, 2 H) 3.50 (ddd, J= 9.71, 6.19, 3.61 Hz, 1 H) 3.43 (spt, J = 6.05 Hz, 1 H) 1.37 (t, J =7.02 Hz, 3 H) 1.02 (dd, J = 6.05, 1.76 Hz, 6 H) 105

1-(3- aminopropyl)-6- (2,4-dimethoxy- 5- methylphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 335.9 1H NMR (400 MHz,DMSO-d6): δ 12.76 (s, 1H), 7.68 (br. s., 3H), 7.11 (s, 1H), 6.74 (s,1H), 5.73 (s, 1H), 4.35-4.45 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H),3.59-3.68 (m, 1H), 2.52-2.51 (m, 2H), 2.09 (s, 3H), 1.81-1.71 (m, 2H).:106

1-(3- aminopropyl)-6- (2,5-dimethoxy- 4- methylphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 336.0 1H NMR (400 MHz,METHANOL-d4): δ 6.91 (s, 1H), 6.79 (s, 1H), 5.72 (s, 1H), 4.40-4.50 (m,1H), 3.78-3.88 (m, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 2.68 (t, 2H), 2.17(s, 3H), 1.89-1.94 (m, 1H), 1.76-1.86 (m, 1H). 107

2-[6-(5-fluoro- 2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]acetamide 339.9 1H NMR (400 MHz, DMSO-d6): δ7.11 (br. s., 1 H), 6.94 (d, 1 H), 6.87 (d, 1 H), 6.83 (br. s., 1 H),5.72 (br. s., 1 H), 5.41 (s, 1 H), 3.91 (s, 3 H), 3.83 (s, 3 H),3.72-3.82 (m, 1 H). 108

1-(3- aminopropyl)-6- (5-fluoro-2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 339.9 1H NMR (400 MHz,DMSO-d6): δ 7.36 (d, 1H), 6.95 (d, 1H), 5.80 (s, 1H), 4.38-4.48 (m, 1H),3.95 (s, 3H), 3.86 (s, 3H), 3.59- 3.67 (m, 1H), 2.45-2.61 (m, 2H),1.67-1.78 (m, 2H).: 109

1-(2- methoxyethyl)- 6-[3- (methylsulfonyl) phenyl]-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 341.0 1H NMR (400 MHz, CHLOROFORM-d) d ppm10.70 (br. s., 1 H), 8.08 (d, J = 7.79 Hz, 1 H), 8.03 (s, 1 H), 7.72(dd, J = 7.80, 7.80 Hz, 1 H), 7.65 (d, J = 7.33 Hz, 1 H), 5.87 (s, 1 H),4.30 (br. s., 2 H), 3.67 (br. s., 2 H), 3.22 (s, 3 H), 3.12 (s, 3 H) 110

1-(2- methoxyethyl)- 6-[4- (methylsulfonyl) phenyl]-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 341.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm8.08 (d, J = 8.24 Hz, 2 H), 7.59 (d, J = 8.24 Hz, 2 H), 5.81 (s, 1 H),4.31 (br. s., 2 H), 3.66 (t, J = 5.04 Hz, 2 H), 3.21 (s, 3 H), 3.14 (s,3 H) 111

1-(2- aminoethyl)-6- (5-chloro-2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 342.0 1H NMR (400 MHz,DMSO-d6) δ ppm 12.87 (br. s, 1 H), 7.80 (br. s, 3 H), 7.48 (s, 1 H),6.94 (s, 1 H), 5.84 (d, J = 1.96 Hz, 1 H), 4.55-4.65 (m, 1 H), 3.97 (s,3 H), 3.90 (s, 3 H), 3.71-3.80 (m, 1 H), 2.86-2.99 (m, 2 H) 112

2-[6-(3- methoxy-2- naphthyl)-4-oxo- 2-thioxo-3,4- dihydropyrimidin-1(2H)- yl]acetamide 342.0 1H NMR (400 MHz, METHANOL-d3) δ ppm 7.84 (d, J= 8.24 Hz, 1 H), 7.81 (d, J = 7.79 Hz, 1 H), 7.79 (s, 1 H), 7.52 (ddd, J= 8.24, 7.10, 1.14 Hz, 1 H), 7.35-7.44 (m, 2 H), 5.89 (s, 1 H),5.42-5.70 (m, 1 H), 4.05-4.26 (m, 1 H), 3.98 (s, 3 H) 113

1-[(2S)-3-amino- 2- hydroxypropyl]- 6-(5-chloro-2- methoxyphenyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one trifluoroacetate 342.1 1H NMR(300 MHz, DMSO-d6) δ ppm 12.84 (s, 1 H), 7.69 (br. s, 3 H), 7.56 (dd, J= 9.06, 2.79 Hz, 1 H), 7.29 (d, J = 2.79 Hz, 1 H), 7.18 (d, J = 9.06 Hz,1 H), 5.87 (d, J = 2.09 Hz, 1 H), 5.74 (d, J = 5.57 Hz, 1 H), 4.55-4.65(m, 1 H), 4.21-4.34 (m, 1 H), 3.83 (s, 3 H), 3.13-3.23 (m, 1 H),2.75-2.88 (m, 2 H) 114

1-[(2R)-3- amino-2- hydroxypropyl]- 6-(5-chloro-2- methoxyphenyl)-2-thioxo-2,3- dihydropyrimidin 4(1H)-one trifluoroacetate 342.2 1H NMR(300 MHz, DMSO-d6) δ ppm 12.84 (s, 1 H), 7.69 (br. s, 3 H), 7.56 (dd, J= 9.06, 2.79 Hz, 1 H), 7.29 (d, J = 2.79 Hz, 1 H), 7.18 (d, J = 9.06 Hz,1 H), 5.87 (d, J = 2.09 Hz, 1 H), 5.74 (d, J = 5.57 Hz, 1 H), 4.55-4.65(m, 1 H), 4.21-4.34 (m, 1 H), 3.83 (s, 3 H), 3.13-3.23 (m, 1 H),2.75-2.88 (m, 2 H) 115

1-(2- methoxyethyl) 6-(1-methoxy-2- naphthyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 343.0 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.54 (br. s., 1 H), 8.11-8.19 (m, 1 H), 7.86-7.95 (m, 1 H), 7.71 (d, J =8.47 Hz, 1 H), 7.61 (dd, J = 6.30, 3.09 Hz, 2 H), 7.28 (d, J = 8.47 Hz,1 H), 5.96 (s, 1 H), 4.67-4.81 (m, 1 H), 4.02 (ddd, J = 14.03, 8.30,5.38 Hz, 1 H), 3.90 (s, 3 H), 3.68-3.78 (m, 1 H), 3.36 (dt, J = 9.90,4.78 Hz, 1 H), 3.06 (s, 3 H) 116

6-(5-chloro-2- methoxyphenyl)- 1-[(2R)-2,3- dihydroxypropyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 343.0 1.942 min (Column:AQUITY BEH C-18, 2.1x50 mm, 1.7 μm; Mobile Phase: A-0.1% FA IN ACN,B-0.1% FA IN WATER; T/% B(min): 0/90, 0.7/90, 2/55, 3/55, 3.8/5, 5.8/5,6/90; Flow: 0.5 mL/min, Diluent: CAN) 117

1-(2- methoxyethyl)- 6-(3-methoxy-2- naphthyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 343.4 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.76 (br. s., 1 H), 7.80 (t, J = 8.36 Hz, 2 H), 7.74 (s, 1 H), 7.55(ddd, J = 8.13, 7.10, 1.03 Hz, 1 H), 7.43 (ddd, J = 8.07, 6.93, 1.03 Hz,1 H), 7.21 (s, 1 H), 5.90 (d, J = 2.06 Hz, 1 H), 4.67-4.77 (m, 1 H),3.95 (s, 3 H), 3.70-3.86 (m, 2 H), 3.34-3.44 (m, 1 H), 3.07 (s, 3 H) 118

1-(2- methoxyethyl)- 2-thioxo-6-[2- (trifluoromethoxy) phenyl]-2,3-dihydropyrimidin- 4(1H)-one 347.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.79 (br. s., 1 H), 7.54-7.63 (m, 1 H), 7.35-7.48 (m, 3 H), 5.86 (s, 1H), 4.57-4.73 (m, 1 H), 3.71- 3.94 (m, 2 H), 3.38-3.49 (m, 1 H), 3.17(s, 3 H) 119

2-{3-[6-(2- methoxy-5- methylphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin- 1(2H)- yl]propyl}guanidine 348.2 1.37 min WatersXBridge C18 4.6x50 mm, 5um 95% H20/ 5% MeCN linear to 5% H20/ 95% MeCNover 4.0 min, HOLD at 5% H20/95% MeCN to 5.0 min. Flow: 2.0 mL/min.NH4OH 0.03%. Flow rate: 2 mL/min 120

N-{2-[6-(2- methoxy-5- methylphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin- 1(2H)- yl]ethyl}glycin- amide hydrochloride 349.2 1HNMR (500 MHz, CD3OD) d ppm 7.37 (d, 1 H), 7.22 (s, 1 H), 7.06 (d, 1 H),5.78 (s, 1 H), 4.81 (m, 1 H), 3.88 (s, 3 H), 3.86 (br. s., 0 H), 3.55(m, 2 H), 3.45 (m, 2 H), 2.36 (s, 3 H) 121

2-{2-[6-(2,5- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]ethyl}guanidine hydrochloride 350. 1 1H NMR (400 MHz, DMSO-d6)δ ppm 12.85 (s, 1 H), 7.61 (br. t, J = 6.10, 6.10 Hz, 1 H), 7.07- 7.12(m, 2 H), 6.98 (br. s., 3 H), 6.93 (d, J = 1.56 Hz, 1 H), 5.85 (d, J =2.15 Hz, 1 H), 4.54 (br. d, J = 14.30 Hz, 1 H), 3.78 (s, 3 H), 3.76 (s,3 H), 3.66-3.75 (m, 1 H), 3.47-3.60 (m, 1 H), 3.15- 3.26 (m, 1 H) 122

6-(5-chloro-2- methoxyphenyl)- 1-[(2R)- pyrrolidin-2- ylmethyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one hydrochloride 352 3.641 minColumn: XBRIDGE- C18 4.6X75 mm 3.5 μm; Mobile phase-A = 0.1% FA IN ACN,B = 0.1% FA IN WATER; Time(min)/% B = 0/90, 0.8/90, 1.8/55, 3/5, 6.5/5,7/90; Flow: 0.8 mL/min, Column Temp = 40° C.; Diluent: CAN 123

6-(5-chloro-2- methoxyphenyl)- 1-[(2S)- pyrrolidin-2- ylmethyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one hydrochloride 352.1 1H NMR (400MHz, DMSO-d6) δ ppm 12.99 (br. s., 1 H), 9.08 (br. s., 1 H), 8.14-8.52(m, 1 H), 7.61-7.67 (m, 1 H), 7.50- 7.58 (m, 1 H), 7.23-7.28 (m, 1 H),5.92-6.00 (m, 1 H), 4.90- 5.04 (m, 1 H), 3.83-3.88 (m, 3 H), 3.63-3.77(m, 1 H), 2.98- 3.20 (m, 3 H), 1.76-1.89 (m, 2 H), 1.62-1.75 (m, 2 H)124

2-[4-oxo-2- thioxo-6-(2,4,5- trimethoxyphenyl)- 3,4- dihydropyrimidin-1(2H)- yl]acetamide 352.1 1.23 min Waters Atlantis dC18 5um 4.6x50 mm,95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95% MeCN to 5.0 min. (0.05% TFA). Flow rate: 2 mL/min 125

1-(3- aminopropyl)-2- thioxo-6-(2,4,5- trimethoxyphenyl)- 2,3-dihydropyrimidin 4(1H)-one hydrochloride 352.1 1H NMR (500 MHz, DMSO-d6)δ ppm 1.70-1.91 (m, 2 H) 2.53- 2.60 (m, 2 H) 3.57 (s, 2 H) 3.69 (d, J =7.07 Hz, 1 H) 3.75 (s, 3 H) 3.83 (s, 3 H) 3.87 (s, 3 H) 4.42 (br. s., 1H) 5.79 (d, J = 1.95 Hz, 1 H) 6.82 (s, 1 H) 7.00 (s, 1 H) 7.86 (br. s.,2 H) 12.76 (s, 1 H) 126

2-{3-[6-(5-fluoro- 2- methoxyphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin- 1(2H)- yl]propyl}guanidine 352.2 1.22 min WatersXBridge C18 4.6x50 mm, 5um; 95% H20/ 5% MeCN linear to 5% H20/ 95% MeCNover 4.0 min, HOLD at 5% H20/95% MeCN to 5.0 min. Flow: 2.0 mL/min.NH4OH 0.03% Flow rate: 2 mL/min 127

N-{2-[6-(5- fluoro-2- methoxyphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin- 1(2H)- yl]ethyl}glycin- amide hydrochloride 353.2 1HNMR (500 MHz, CD₃OD) d ppm 7.30 (td, 1 H), 7.25 (dd, 1 H), 7.16 (dd, 1H), 5.81 (s, 1 H), 4.79 (m, 1 H), 3.89 (s, 3 H), 3.82 (m, 1 H), 3.54 (m,2 H), 3.45 (m, 2 H) 128

2-{2-[6-(5- chloro-2- methoxyphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin 1(2H)- yl]ethyl}guanidine hydrochloride 354.0 1H NMR(500 MHz, DMSO-d6) δ ppm 12.88 (s, 1 H), 7.63 (br. s., 1 H), 7.58 (dd, J= 9.03, 2.68 Hz, 1 H), 7.39-7.41 (m, 1 H), 7.20 (d, J = 9 03 Hz, 1 H), 700 (br. s., 4 H), 5.91 (d, J = 2.20 Hz, 1 H), 4.54 (br. d, J = 13.40 Hz,1 H), 3.84 (s, 3 H), 3.59-3.67 (m, 1 H), 3.55 (dt, J = 9.33, 4.97 Hz, 1H), 3.17-3.25 (m, 1 H) 129

1-(3- aminopropyl)-6- (5-chloro-2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 356.0 1H NMR (400 MHz,DMSO-d6) δ ppm 12.78 (s, 1 H), 7.75 (br. s., 3 H), 7.49 (s, 1 H), 6.92(s, 1 H), 5.83 (d, J = 2.45 Hz, 1 H), 4.32-4.45 (m, 1 H), 3.97 (s, 3 H),3.90 (s, 3 H), 3.59-3.70 (m, 1 H), 2.53-2.65 (m, 2 H), 1.66- 1.88 (m, 2H) 130

1-(2-{4-oxo-2- thioxo-6-[2-(2H- 1,2,3-triazol-2- yl)phenyl]-3,4-dihydropyrimidin- 1(2H)- yl}ethyl)guanidine hydrochloride 357.1 1H NMR(400 MHz, METHANOL-d4): δ 8.12 (d, 1H), 7.91 (s, 2H), 7.75 (t, 1H),7.55-7.59 (m, 2H), 5.74 (s, 1H), 4.40 (m, 1H), 3.75 (m, 1H), 3.55 (m,1H), 3.35 (m, 1H). 131

2-{3-[6-(2,5- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]propyl}guanidine trifluoroacetate 364.1 2.44 min WatersAtlantis dC18 5um 4.6x50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCNover 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05% TFA). Flowrate: 2 mL/min 132

6-(5-chloro-2- methoxyphenyl)- 1-(piperidin-4- ylmethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 366.0 3.639 min Column:XBRIDGE- C18 4.6X75 mm 3.5 μm Mobile phase-A = 0.1% FA IN ACN, B = 0.1%FA IN WATER Time(min)/% B = 0/90, 0.8/90, 1.8/55, 3/5, 6.5/5, 7/90 Flow:0.8 mL/min, Column Temp = 40° C.; Diluent: MEOH 133

2-{3-[6-(5- chloro-2- methoxyphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin- 1(2H)- yl]propyl}guanidine 368.1 1.38 min WatersXBridge C18 4.6x50 mm, 5um 95% H20/ 5% MeCN linear to 5% H20/ 95% MeCNover 4.0 min, HOLD at 5% H20/95% MeCN to 5.0 min. Flow: 2.0 mL/min.NH4OH 0.03% Flow rate: 2 mL/min 134

N-{3-[6-(5- chloro-2- methoxyphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin- 1(2H)- yl]propyl}acetamide 368.1 1H NMR (400 MHz,DMSO-d6) d ppm 12.73 (s, 1 H), 7.62 (t, J = 6.0 Hz, 1 H), 7.58 (dd, J =9.0, 2.7 Hz, 1 H), 7.50 (d, J = 2.7 Hz, 1 H), 7.21 (s, 0 H), 5.83 (d, J= 2.1 Hz, 1 H), 4.12-4.27 (m, 1 H), 3.85 (s, 3 H), 3.58-3.70 (m, 1 H),2.78 (q, J = 6.2 Hz, 2 H), 1.65-1.75 (m, 0 H), 1.61 (s, 3 H), 1.46-1.58(m, 1 H) 135

N-{2-[6-(5- chloro-2- methoxyphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin- 1(2H)- yl]ethyl}glycin- amide hydrochloride 369.2 1HNMR (400 MHz, CD₃OD) d ppm 7.54 (dd, 1 H), 7.46 (d, 1 H), 7.17 (d, 1 H),5.81 (s, 1 H), 4.78 (m, 1 H), 3.91 (s, 3 H), 3.80 (m, 1 H), 3.55 (m, 2H), 3.46 (t, 2 H) 136

1-cyano-3-{2-[6- (2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]ethyl}guanidine 375.0 1H NMR (400 MHz,DMSO-d6): δ 7.17 (d, 1 H), 6.70-6.88 (br, 1 H), 6.55-6.65 (m, 4 H), 5.69(s, 1 H), 4.43-4.45 (m, 1 H), 3.88 (s, 3 H), 3.84 (s, 3 H), 3.59-3.68(m, 1 H), 3.30-3.40 (m, 1H), 3.16-3.17 (m, 1 H). 137

tert-butyl [6- (2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]acetate 379.1 2.59 min Waters XBridge C184.6x50 mm, 5um 95% H20/ 5% MeCN linear to 5% H20/ 95% MeCN over 4.0 min,HOLD at 5% H20/95% MeCN to 5.0 min. Flow: 2.0 mL/min. NH4OH 0.03% Flowrate: 2 mL/min 138

2-{2-[4-oxo-2- thioxo-6-(2,4,5- trimethoxyphenyl)- 3,4-dihydropyrimidin- 1(2H)- yl]ethyl}guanidine hydrochloride 380.1 1H NMR(500 MHz, DMSO-d6) δ ppm 12.80 (d, J = 1.71 Hz, 1 H), 7.59 (t, J = 6.10Hz, 1 H), 6.98 (br. s., 4 H), 6.89 (s, 1 H), 6.80 (s, 1 H), 5.81 (d, J =2.20 Hz, 1 H), 4.54 (br. d, J = 14.15 Hz, 1 H), 3.86 (s, 3 H), 3.82 (s,3 H), 3.77-3.81 (m, 1 H), 3.75 (s, 3 H), 3.53 (ddt, J = 14.45, 8.72,5.49, 5.49 Hz, 1 H), 3.15- 3.25 (m, 1 H) 139

ethyl [4-oxo-2- thioxo-6-(2,4,5- trimethoxyphenyl)- 3,4-dihydropyrimidin- 1(2H)- yl]acetate 381.1 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 9.60 (br. s., 1 H), 6.71 (s, 1 H), 6.52 (s, 1 H), 5.86 (s, 1 H),5.39 (br. d, J = 17.40 Hz, 1 H), 4.24 (br. d, J = 17.80 Hz, 1 H),4.02-4.18 (m, 2 H), 3.93 (s, 3 H), 3.81 (s, 3 H), 3.79 (s, 3 H), 1.18(t, J = 7.13 Hz, 3 H) 140

1-(2-{2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]ethoxy}ethyl) guanidine formate 393.8 1H NMR(400 MHz, METHANOL-d4): δ 8.38 (br. s., 1H), 7.21 (d, 1H), 6.66-6.62 (m,2H), 5.73 (s, 1H), 4.82-4.76 (m, 1H), 3.93-3.81 (m, 7H), 3.77- 3.71 (m,1H), 3.57-3.51 (m, 1H), 3.44-3.40 (m, 2H), 3.27- 3.22 (m, 2H). 141

2-{3-[4-oxo-2- thioxo-6-(2,4,5- trimethoxyphenyl)- 3,4- dihydropyrimidin1(2H)- yl]propyl}guanidine trifluoroacetate 394.1 1.60 min WatersAtlantis dC18 5um 4.6x50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCNover 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05% TFA). Flowrate: 2 mL/min 142

1-(2- aminoethyl)-6- (1H-indol-4-yl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one trifluoroacetate 270.1 [M − NH3 + 1]+ 1H NMR (300 MHz,METHANOL-d4) δ ppm 11.13 (br. s., 1 H), 7.62 (d, J = 8.01 Hz, 1 H), 7.44(d, J = 3.14 Hz, 1 H), 7.29 (t, J = 7.66 Hz, 1 H), 7.13 (d, J = 7.32 Hz,1 H), 6.40 (d, J = 2.44 Hz, 1 H), 5.93 (s, 1 H), 4.70-4.81 (m, 1 H),4.32 (dt, J = 14.28, 7.14 Hz, 1 H), 2.91- 3.11 (m, 2 H) 143

1-(2- aminoethyl)-6- (1-benzofuran- 7-yl)-2-thioxo- 2,3-dihydropyrimidin- 4(1H)-one hydrochloride 270.9 [M − NH3 + 1]+ 1H NMR(400 MHz, DMSO-d6) δ ppm 13.01 (br. s, 1 H), 8.13 (d, J = 1.96 Hz, 1 H),7.90 (dd, J = 7.34, 1.96 Hz, 1 H), 7.67 (br. s, 3 H), 7.42-7.49 (m, 2H), 7.14 (d, J = 2.45 Hz, 1 H), 6.04 (s, 1 H), 4.57-4.73 (m, 1 H),3.85-4.02 (m, 1 H), 3.03-3.09 (m, 1 H), 2.83-2.91 (m, 1 H) 144

1-(2- aminoethyl)-2- thioxo-6-[2-(2H- 1,2,3-triazol-2- yl)phenyl]-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 297.9 [M − NH3 + 1]+ 1H NMR(400 MHz, METHANOL-d4): δ 8.11 (d, 1H), 7.90 (s, 2H), 7.74 (t, 1H), 7.60(d, 2H), 5.62 (s, 1H), 4.67 (m, 1H), 4.10 (m, 1H), 3.28 (m, 1H), 3.05(s, 1H).: 145

2-[6-(5-chloro-2- methoxypyridin- 3-yl)-4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]acetamide 325.0 [M − H]− 1H NMR (400 MHz,METHANOL-d4) δ ppm 8.31 (s, 1 H), 7.72 (s, 1 H), 5.88 (s, 1 H),5.56-5.72 (m, 1 H), 4.06- 4.21 (m, 1 H), 3.95 (s, 3 H) 146

2-[6-(2,4- dimethoxy-5- methylphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin- 1(2H)- yl]acetamide 358.0 [M + Na]⁺ 1H NMR (400 MHz,DMSO-d6): δ 12.55 (br, 1 H), 7.31 (s, 1 H), 7.02 (s, 1 H), 6.92 (s, 1H), 6.72 (s, 1 H), 5.72 (s, 1 H), 5.35 (br. s., 1 H), 3.93 (br. s., 1H), 3.88 (s, 3 H), 3.85 (s, 3 H), 2.05 (s, 3 H). 147

2-[6-(2,5- dimethoxy-4- methylphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin- 1(2H)- yl]acetamide 358.0 [M + Na]+ 1H NMR (400 MHz,METHANOL-d4): δ 6.86 (s, 1H), 6.69 (s, 1H), 5.72 (s, 1H), 4.57 (m, 1H),4.10 (m, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 2.16 (s, 3H). 148

1-{3-[6-(5- chloro-2- methoxyphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin- 1(2H)- yl]propyl}urea 367.2 [M − 1]⁻ 1H NMR (500 MHz,DMSO-d6) d ppm 12.72 (br. s, 1 H), 7.57 (dd, J = 9.0, 2.7 Hz, 1 H), 7.52(d, J = 2.7 Hz, 1 H), 7.19 (d, J = 9.0 Hz, 1 H), 5.84 (s, 1 H), 5.75 (m,1 H), 5.26 (s, 2 H), 4.26 (m, 1 H), 3.84 (s, 3 H), 3.61 (m, J = 10.0 Hz,1 H), 2.72 (m, 2 H), 1.65 (m, 1 H), 1.49 (dd, J = 11.6, 5.7 Hz, 1 H) 149

N-{3-[6-(5- chloro-2- methoxyphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin- 1(2H)- yl]propyl}glycin- amide hydrochloride 381.2 [M− 1]⁻ 1H NMR (500 MHz, DMSO-d6) d ppm 8.29 (t, J = 5.6 Hz, 1 H),7.87-8.16 (m, 2 H), 7.60 (dd, J = 9.0, 2.7 Hz, 1 H), 7.53 (d, J = 2.7Hz, 1 H), 7.23 (d, J = 9.0 Hz, 1 H), 5.87 (s, 1 H), 4.17- 4.32 (m, 1 H),3.84 (s, 3 H), 3.56-3.73 (m, 1 H), 3.34-3.42 (m, 2 H), 2.80-3.00 (m, 2H), 1.74 (d, J = 6.6 Hz, 1 H), 1.55- 1.64 (m, 1 H) 150

1-(2- hydroxyethyl)-6- (2-methoxy-5- methylpyridin-3- yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 293.8 1H NMR (400 MHz, CD3OD) d ppm 8.14 (m,1 H), 7.59 (d, 1 H), 5.78 (d, 1 H), 4.71 (m, 1 H), 3.96 (d, 3 H), 3.85(dt, 1 H), 3.70 (dt, 1 H), 3.59 (m, 1 H), 2.32 (s, 3 H)

The following Examples of Table 3 were prepared from the correspondingmethyl ketone to afford the intermediate beta-keto-ester as describedabove for the Preparations in the Methyl Ketone Route section followedby employing other methods described in the I. Beta Ketone Ester RouteSection as well as standard methods and techniques known to thoseskilled in the art.

TABLE 3 Examples from Methyl Ketone Route Ex- 1H NMR Spectral Data orample Compound Obs HPLC Retention Time and # Structure Name MassConditions 151

6-(2,4- dimethoxyphenyl)- 1-[(3R)- piperidin-3- ylmethyl]-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 362.0 3.653 min Column:XBRIDGE- C18 4.6X75 mm 3.5 μm Mobile phase-A = 0.1% FA IN ACN, B = 0.1%FA IN WATER Time(min)/% B = 0/90, 0.8/90, 1.8/55, 3/5, 6.5/5, 7/90 Flow:0.8 mL/min, Column Temp = 40° C.; Diluent: CAN 152

6-(2,4- dimethoxyphenyl)- 1-(2-piperidin- 4-ylethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 376.1 1HNMR (400 MHz,METHANOL-d4): δ 7.26 (d, 1H), 6.70 (d, 1H), 6.67 (dd, 1H), 5.76 (s, 1H),4.56-4.67 (m, 1H), 3.88 (s, 3H), 3.8 (s, 3H), 3.72- 3.80 (m, 1H),3.22-3.25 (m, 2H), 2.82-2.89 (t, 2H), 1.63- 1.75 (m, 3H), 1.341.48 (m,2H), 1.08-1.29 (m, 2H). 153

1-[2-(1- acetylpiperidin- 4-yl)ethyl]-6- (2,4- dimethoxyphenyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 440.1 [M + Na]+ 1HNMR (400MHz, METHANOL-d4): δ 7.25 (d, 1H), 6.71 (d, 1H), 6.68 (dd, 1H), 5.75 (s,1H), 4.52-4.65 (m, 1H), 4.27-4.35 (m, 1H), 3.88 (s, 6H), 3.70-3.80 (m,2H), 2.92-3.03 (m, 1H), 2.49-2.56 (m, 1H), 2.05 (s, 3H), 1.71-1.74 (m,1H), 1.33-1.57 (m, 4H), 0.68-1.10 (m, 2H). 154

6-(1H-imidazol- 2-yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 253.1 1H NMR (400 MHz, METHANOL-d3) δ ppm7.26 (br. s., 2 H), 6.04 (s, 1 H), 4.84 (br. s., 2 H), 3.63 (t, J = 5.27Hz, 2 H), 3.13 (s, 3 H) 155

1-(2- hydroxyethyl)-6- (3- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 279.1 1H NMR (400 MHz, METHANOL-d3) δ ppm7.43 (dd, J = 7.80, 7.80 Hz, 1 H), 7.08 (ddd, J = 8.47, 2.52, 0.92 Hz, 1H), 7.04 (dd, J = 2.29, 2.29 Hz, 1 H), 7.00 (ddd, J = 7.80, 2.30, 0.92Hz, 1 H), 5.79 (s, 1 H), 4.26-4.39 (m, 2 H), 3.84 (s, 3 H), 3.77 (t, J =6.18 Hz, 2 H) 156

1-(2- hydroxyethyl)-6- (2- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 279.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.51 (ddd, J = 8.24, 7.30, 1.80 Hz, 1 H), 7.25 (dd, J = 7.56, 1.60 Hz, 1H), 7.08 (ddd, J = 7.60, 7.60, 0.90 Hz, 1 H), 7.00 (d, J = 8.24 Hz, 1H), 5.86 (s, 1 H), 4.70- 4.79 (m, 1 H), 3.83-3.91 (m, 5 H), 3.64-3.72(m, 1 H) 157

6-(2,6- dimethoxyphenyl)- 1-methyl-2- thioxo-2,3- dihydropyrimidin-4(1H)-one 279.2 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.00 (br. s., 1H), 7.40 (t, J = 7.79 Hz, 1 H), 6.62 (d, J = 8.24 Hz, 2 H), 5.85 (s, 1H), 3.80 (s, 6 H), 3.45 (s, 3 H) 158

6-(2- fluorophenyl)-1- (2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 281.1 1H NMR (400 MHz, METHANOL-d3) δ ppm7.54- 7.63 (m, 1 H), 7.47 (ddd, J = 7.60, 7.60, 1.80 Hz, 1 H), 7.35(ddd, J = 7.80, 7.80, 1.40 Hz, 1 H), 7.29 (ddd, J = 9.85, 8.47, 0.92 Hz,1 H), 5.86 (s, 1 H), 4.64 (dt, J = 14.08, 4.64 Hz, 1 H), 3.99-4.12 (m, 1H), 3.70 (ddd, J = 10.53, 7.33, 5.04 Hz, 1 H), 3.48 (dt, J = 10.42, 5.09Hz, 1 H), 3.11 (s, 3 H) 159

1-(2- aminoethyl)-6- (2-methoxy-5- methylphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 292 1H NMR (500 MHz, DMSO-d6)δ ppm 12.80-12.90 (m, 1 H) 7.95 (br. s., 3 H) 7.36 (dd, J = 8.42, 1.83Hz, 1 H) 7.18 (d, J = 1.95 Hz, 1 H) 7.10 (d, J = 8.54 Hz, 1 H) 5.78 (d,J = 2.20 Hz, 1 H) 4.54-4.65 (m, 1 H) 3.86- 3.96 (m, 1 H) 3.81 (s, 3 H)2.82- 2.95 (m, 2 H) 2.29 (s, 3 H) 160

1-(2- methoxyethyl)- 6-(2- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 293.1 1H NMR (400 MHz, METHANOL-d3) d ppm7.53 (ddd, J = 8.00, 8.00, 1.80 Hz, 1 H), 7.32 (dd, J = 7.33, 1.83 Hz, 1H), 7.14 (d, J = 8.70 Hz, 1 H), 7.09 (ddd, J = 7.60, 7.60, 0.90 Hz, 1H), 5.75 (s, 1 H), 4.71 (ddd, J = 13.74, 5.95, 4.12 Hz, 1 H), 3.89 (s, 3H), 3.80-3.88 (m, 1 H), 3.68 (ddd, J = 10.53, 7.79, 5.95 Hz, 1 H), 3.43(ddd, J = 10.42, 6.53, 4.12 Hz, 1 H), 3.08 (s, 3 H) 161

1-(2- hydroxyethyl)-6- (2-methoxy-5- methylphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 293.2 1H NMR (400 MHz, DMSO-d6) δ ppm 12.71(br. s, 1 H) 7.32 (ddd, J = 8.39, 2.15, 0.59 Hz, 1 H) 7.14 (d, J = 2.15Hz, 1 H) 7.06 (d, J = 8.39 Hz, 1 H) 5.72 (d, J = 2.15 Hz, 1 H) 4.70 (t,J = 5.56 Hz, 1 H) 4.43-4.51 (m, 1 H) 3.79 (s, 3 H) 3.55-3.64 (m, 1 H)3.47-3.55 (m, 1 H) 3.38-3.46 (m, 1 H) 2.28 (s, 3 H) 162

1-(2- hydroxyethyl)-6- (1-naphthyl)-2- thioxo-2,3- dihydropyrimidin-4(1H)-one 299.1 1H NMR (400 MHz, DMSO-d6) δ ppm 12.82 (br. s., 1 H),7.99- 8.13 (m, 2 H), 7.67-7.73 (m, 1 H), 7.52-7.66 (m, 4 H), 5.87 (d, J= 1.76 Hz, 1 H), 4.61 (br. s., 1 H), 4.23-4.37 (m, 1 H), 3.34- 3.51 (m,3 H) 163

3-[3-(2- hydroxyethyl)-6- oxo-2-thioxo- 1,2,3,6- tetrahydropyrimi-din-4-yl]-4- methoxybenzo- nitrile 304.2 1H NMR (500 MHz, DMSO-d6) δ ppm12.80 (s, 1 H) 8.03 (dd, J = 8.78, 1.95 Hz, 1 H) 7.82 (d, J = 2.20 Hz, 1H) 7.36 (d, J = 8.78 Hz, 1 H) 5.87 (d, J = 2.20 Hz, 1 H) 4.46-4.54 (m, 1H) 3.92 (s, 3 H) 3.57-3.64 (m, 1 H) 3.38- 3.49 (m, 2 H) 164

2-[6-(2- methoxy-5- methylphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin- 1(2H)- yl]acetamide 306.0 1.44 min Waters AtlantisdC18 5um 4.6x50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05% TFA). Flow rate: 2mL/min 165

6-[6- (dimethylamino) pyridin-3-yl]-1- (2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 307.2 1H NMR (400 MHz, METHANOL-d3) δ ppm8.07 (d, J = 1.83 Hz, 1 H), 7.99 (dd, J = 9.62, 2.29 Hz, 1 H), 7.28 (d,J = 9.62 Hz, 1 H), 5.90 (s, 1 H), 4.40 (br. s., 2 H), 3.71 (t, J = 5.04Hz, 2 H), 3.33 (s, 6 H), 3.26 (s, 3 H) 166

1-(2- aminoethyl)-6- (2,5- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 308.0 1H NMR (400 MHz,DMSO-d6) δ ppm 12.87 (s, 1 H) 7.93 (br. s., 3 H) 7.09-7.16 (m, 2 H) 7.03(d, J = 2.73 Hz, 1 H) 5.82 (d, J = 1.95 Hz, 1 H) 4.54-4.64 (m, 1 H)3.86-3.98 (m, 1 H) 3.79 (s, 3 H) 3.75 (s, 3 H) 2.85- 2.97 (m, 2 H) 167

6-(2,6- dimethoxyphenyl)- 1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 309.0 1H NMR (400 MHz, DMSO-d6) δ ppm 12.72(br. s., 1 H), 7.45 (t, J = 8.36 Hz, 1 H), 6.79 (d, J = 8.47 Hz, 2 H),5.71 (d, J = 2 06 Hz, 1 H), 3.94 (t, J = 7.21 Hz, 2 H), 3.76 (s, 6 H),3.35 (t, J = 7.56 Hz, 2 H) 168

6-[2-(2- hydroxyethoxy) phenyl]-1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 309.1 1.57 min Waters Atlantis dC18 5um4.6x50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLDat 5% H2O/95% MeCN to 5.0 min. (0.05% TFA). Flow rate: 2 mL/min 169

6-(2,5- dimethoxyphenyl)- 1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 309.2 1H NMR (500 MHz, DMSO-d6) δ ppm 12.72(s, 1 H) 7.06-7.11 (m, 2 H) 6.95 (d, J = 2.44 Hz, 1 H) 5.77 (d, J = 2.20Hz, 1 H) 4.72 (t, J = 5.61 Hz, 1 H) 4.44- 4.50 (m, 1 H) 3.77 (s, 3 H)3.74 (s, 3 H) 3.51-3.64 (m, 2 H) 3.40-3.46 (m, 1 H) 170

2-[6-(5-cyano-2- methoxyphenyl)- 4-oxo-2-thioxo- 3,4- dihydropyrimidin-1(2H)- yl]acetamide 317.2 1H NMR (500 MHz, DMSO-d6) δ ppm 3.76-3.94 (m,2 H), 3.93 (s, 3 H), 5.92 (d, J = 1.7 Hz, 1 H), 7.10 (br. s., 1 H), 7.31(br. s., 1 H), 7.37 (d, J = 8.8 Hz, 1 H), 7.61 (s, 1 H), 8.03 (dd, J =8.7, 1.6 Hz, 1 H), 12.88 (br. s., 1 H) 171

4-methoxy-3-[3- (2- methoxyethyl)- 6-oxo-2-thioxo- 1,2,3,6-tetrahydropyrimi- din-4- yl]benzonitrile 318.1 2.34 min Waters AtlantisdC18 5um 4.6x50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05% TFA). Flow rate: 2mL/min 172

1-(2- isopropoxyethyl)- 6-(4- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 321.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm10.19 (br. s., 1 H) 7.29 (d, J = 8.78 Hz, 2 H) 6.97 (d, J = 8.97 Hz, 2H) 5.84 (d, J = 2.15 Hz, 1 H) 4.37 (t, J = 5.46 Hz, 2 H) 3.87 (s, 3 H)3.68 (t, J = 5.66 Hz, 2 H) 3.47 (spt, J = 6.08 Hz, 1 H) 1.06 (d, J =6.05 Hz, 6 H) 173

1-(2- isopropoxyethyl)- 6-(2- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 321.5 1H NMR (400 MHz, METHANOL-d4) δ ppm7.53 (ddd, J = 8.39, 7.61, 1.76 Hz, 1 H) 7.33 (dd, J = 7.41, 1.76 Hz, 1H) 7.13 (d, J = 8.58 Hz, 1 H) 7.08 (ddd, J = 7.51, 7.51, 0.98 Hz, 1 H)5.75 (s, 1 H) 4.69 (ddd, J = 13.51, 6.58, 3.90 Hz, 1 H) 3.88 (s, 3 H)3.78 (dt, J = 13.61, 7.34 Hz, 1 H) 3.64- 3.72 (m, 1 H) 3.50 (ddd, J =9.80, 7.07, 4.00 Hz, 1 H) 3.38 (spt, J = 6.11 Hz, 1 H) 0.99 (dd, J =6.15, 2.44 Hz, 6 H) 174

2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]acetamide 322.2 1H NMR (500 MHz, DMSO-d6) δ ppm 12.75 (s, 1 H)7.31 (br. s., 1 H) 7.08 (d, J = 8.54 Hz, 1 H) 6.98 (br. s., 1 H) 6.69(d, J = 2.20 Hz, 1 H) 6.61 (dd, J = 8.54, 2.20 Hz, 1 H) 5.74 (s, 1 H)5.38 (br. s., 1 H) 3.87 (br. s., 1 H) 3.82 (s, 3 H) 3.81 (s, 3 H) 175

1-[(2R)-2- aminopropyl]-6- (2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 322.1 1H NMR (400 MHz,METHANOL-d3) δ ppm 7.21- 7.31 (m, 1 H), 6.71 (d, J = 1.83 Hz, 1 H), 6.68(dd, J = 8.24, 2.29 Hz, 1 H), 5.77-5.85 (m, 1 H), 5.10-5.24 (m, 1 H),3.87-3.90 (m, 3 H), 3.83-3.86 (m, 3 H), 3.61-3.73 (m, 1 H), 3.47-3.59(m, 1 H), 0.90-1.15 (m, 3 H) 176

1-[(2S)-2- aminopropyl]-6- (2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 322.1 1H NMR (400 MHz,METHANOL-d3) δ ppm 7.24- 7.33 (m, 1 H), 6.67-6.76 (m, 2 H), 5.80-5.85(m, 1 H), 5.13- 5.25 (m, 1 H), 3.87-3.92 (m, 6 H), 3.51-3.76 (m, 2 H),0.95- 1.16 (m, 3 H) 177

6-(2,4- dimethoxyphenyl)- 1-[2- (methylamino) ethyl]-2-thioxo- 2,3-dihydropyrimidin- 4(1H)-one formate 322.1 1H NMR (400 MHz, METHANOL-d3)δ ppm 7.27 (d, J = 8.24 Hz, 1 H), 6.73 (d, J = 2.29 Hz, 1 H), 6.70 (dd,J = 8.47, 2.52 Hz, 1 H), 5.81 (s, 1 H), 4.06-4.17 (m, 2 H), 3.90 (s, 3H), 3.87 (s, 3 H), 2.99- 3.16 (m, 2 H), 2.55 (s, 3 H) 178

1-(3- aminopropyl)-6- (2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one formate 322.1 1H NMR (400 MHz, DMSO-d6) δppm 8.29 (s, 1 H), 7.25 (d, J = 8.70 Hz, 1 H), 6.68 (d, J = 2.29 Hz, 1H), 6.62 (dd, J = 8.24, 2.29 Hz, 1 H), 5.72 (s, 1 H), 4.31-4.45 (m, 2H), 3.80 (s, 3 H), 3.79 (s, 3 H), 3.16- 3.62 (m, 3 H), 2.39-2.44 (m, 2H), 1.52-1.81 (m, 2 H) 179

6-(2,4- dimethoxyphenyl)- 1-(2- hydroxypropyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 323.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.57- 9.72 (m, 1 H), 7.11-7.21 (m, 1 H), 6.45-6.60 (m, 2 H), 5.82 (dd, J= 13.05, 2.52 Hz, 1 H), 4.41-4.93 (m, 1 H), 4.27-4.41 (m, 1 H), 3.86 (s,3 H), 3.82 (m, 3 H), 3.53-3.69 (m, 1 H), 0.94- 1.05 (m, 3 H) 180

6-(2,6- dimethoxyphenyl)- 1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 323.1 2.50 min Waters Atlantis dC18 5um4.6x50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLDat 5% H2O/95% MeCN to 5.0 min. (0.05% TFA). Flow rate: 2 mL/min 181

6-(2,4- dimethoxyphenyl)- 1-(3- hydroxypropyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 323.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.46 (br. s., 1 H), 7.11 (d, J = 8.24 Hz, 1 H), 6.56 (dd, J = 8.24, 2.29Hz, 1 H), 6.52 (d, J = 2.29 Hz, 1 H), 5.82 (d, J = 2.75 Hz, 1 H), 4.64-4.75 (m, 1 H), 3.86 (s, 3 H), 3.82 (s, 3 H), 3.80-3.89 (m, 2H), 3.49 (t,J = 5.72 Hz, 1 H), 1.56- 1.83 (m, 2 H) 182

6-(2,4- dimethoxyphenyl)- 1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 323.2 1H NMR (300 MHz, CDCl3) 9.80 (bs, 1H),7.13 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.50 (s, 1H), 5.80(d, J = 2.1Hz, 1H), 4.70 (dt, J = 13.5, 4.5 Hz, 1H), 3.86 (s, 3H),3.83-3.91 (m, 1H) 3.82 (s, 3H), 3.66-3.74 (m, 1H), 3.41-3.47 (m, 1H),3.16 (s, 3H) 183

1-(2- aminoethyl)-6- (3- bromophenyl)-2- thioxo-2,3- dihydropyrimidin-4(1H)-one hydrochloride M + 1 (− NH2) = 311.0 1H NMR (500 MHz, DMSO-d6)d ppm 12.88 (br. s., 1 H), 7.86 (br. s., 2 H), 7.82 (s, 1 H), 7.77 (d, J= 7.8 Hz, 1 H), 7.56 (m, 1 H), 7.51 (m, 1 H), 5.87 (s, 1 H), 4.26 (br.s., 2 H), 2.94 (m, 2 H) 184

6-(5-fluoro-2,4- dimethoxyphenyl)- 1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 326.8 1H NMR (400 MHz, CD₃OD) d ppm 7.12(dd, 1 H), 6.85 (d, 1 H), 5.75 (d, 1 H), 4.60-4.73 (m, 1 H), 3.97 (s, 3H), 3.90 (s, 3 H), 3.76-3.86 (m, 2 H), 3.56- 3.65 (m, 1 H) 185

1-(2- aminoethyl)-6- (4-methoxy-1- naphthyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 327.9 1H NMR (400 MHz,DMSO-d6) δ ppm 12.92 (br. s, 1 H), 8.24 (dd, J = 7.44, 1.95 Hz, 1 H),7.73 (d, J = 7.33 Hz, 1 H), 7.49-7.65 (m, 6 H), 7.08 (d, J = 8.01 Hz, 1H), 5.89 (s, 1 H), 4.47 (ddd, J = 13.91, 8.87, 5.15 Hz, 1 H), 4.01 (s, 3H), 3.66-3.77 (m, 1 H), 2.82-2.91 (m, 1 H), 2.77 (ddd, J = 12.31, 8.87,6.30 Hz, 1 H) 186

1-(2- hydroxyethyl)-2- thioxo-6-[2- (trifluorometh- oxy)phenyl]-2,3-dihydropyrimidin- 4(1H)-one 333.0 1H NMR (400 MHz, CDCl3): δ 9.89 (br.s., 1H), 7.63-7.58 (m, 1H), 7.45-7.40 (m, 3H), 5.89 (d, 1H), 4.74-4.67(m, 1H), 4.01- 3.95 (m, 1H), 3.82-3.75 (m, 1H), 3.71-3.66 (m, 1H), 1.83(s, 1H). 187

3-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]propanimid- amide trifluoroacetate 335.1 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.23 (d, J = 8.22 Hz, 1 H), 6.71 (d, J = 2.15 Hz, 1H), 6.68 (dd, J = 8.41, 2.15 Hz, 1 H), 5.78 (s, 1 H), 4.97 (dt, J =14.57, 5.72 Hz, 1 H), 3.99-4.07 (m, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H),2.87 (ddd, J = 14.48, 8.22, 5.50 Hz, 1 H), 2.62-2.72 (m, 1 H) 188

2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]propanamide 336.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.79(br. s., 1 H), 7.11-7.25 (m, 1 H), 6.48-6.64 (m, 2 H), 5.85- 5.91 (m, 1H), 5.42-5.75 (m, 2 H), 4.35-4.76 (m, 1 H), 3.85- 3.90 (m, 3 H),3.81-3.85 (m, 3 H), 1.85 (m, J = 6.87 Hz, 3 H) 189

3-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]propanamide 336.1 1H NMR (400 MHz, DMSO-d6) δ ppm 12.66 (br.s, 1 H), 7.23 (d, J = 8.70 Hz, 1 H), 7.21 (br. s., 1 H), 6.72 (br. s., 1H), 6.67 (d, J = 2.29 Hz, 1 H), 6.60 (dd, J = 8.24, 2.29 Hz, 1 H), 5.69(s, 1 H), 4.31-4.44 (m, 2 H), 3.79 (s, 3 H), 3.78 (s, 3 H) 190

2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]-N- methylacetamide 336.2 1H NMR (400 MHz, DMSO-d6) δ ppm 12.77(br. s., 1 H), 7.75 (d, J = 4.58 Hz, 1 H), 7.07 (d, J = 8.24 Hz, 1 H),6.67 (d, J = 2.29 Hz, 1 H), 6.60 (dd, J = 8.47, 2.06 Hz, 1 H), 5.75 (s,1 H), 5.24-5.43 (m, 1 H), 3.87- 3.99 (m, 1 H), 3.81 (s, 3 H), 3.78-3.81(m, 3 H), 2.45 (d, J = 4.58 Hz, 3 H) 191

1-(4- aminobutyl)-6- (2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 335.9 1H NMR (300 MHz,DMSO-d6) δ ppm 12.73 (br. s., 1 H), 7.85 (br. s., 3 H), 7.31 (d, J =8.36 Hz, 1 H), 6.72 (d, J = 2.09 Hz, 1 H), 6.66 (dd, J = 8.36, 2.79 Hz,1 H), 5.75 (d, J = 2.09 Hz, 1 H), 4.29- 4.48 (m, 1 H), 3.84 (s, 3 H),3.83 (s, 3 H), 3.45-3.50 (m, 1 H), 2.53-2.62 (m, 2 H), 1.38- 1.66 (m, 2H), 1.21-1.37 (m, 2 H) 192

6-(2,4- dimethoxyphenyl)- 1-[3- (methylamino) propyl]-2-thioxo- 2,3-dihydropyrimidin- 4(1H)-one hydrochloride 336.1 1H NMR (400 MHz,DMSO-d6) δ ppm 12.75 (br. s., 1 H), 8.38 (br. s., 2 H), 7.28 (d, J =8.24 Hz, 1 H), 6.69 (d, J = 2.06 Hz, 1 H), 6.63 (dd, J = 8.47, 2.29 Hz,1 H), 5.73 (d, J = 2.06 Hz, 1 H), 4.32- 4.44 (m, 1 H), 3.80 (s, 6 H),3.52-3.63 (m, 1 H), 3.28 (s, 3 H), 2.39 (t, J = 4.92 Hz, 2 H), 1.63-1.92(m, 2 H) 193

3-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]propanoic acid 337.1 1H NMR (400 MHz, DMSO-d6) δ ppm 12.76(br. s., 1 H), 7.30 (d, J = 8.70 Hz, 1 H), 6.70 (d, J = 2.29 Hz, 1 H),6.65 (dd, J = 8.70, 2.29 Hz, 1 H), 5.74 (s, 1 H), 4.38-4.51 (m, 1 H),3.82 (s, 3 H), 3.82-3.87 (m, 1 H), 3.82 (s, 3 H), 2.53-2.63 (m, 1 H),2.40-2.48 (m, 1 H) 194

6-(2,4- dimethoxyphenyl)- 1-(2-hydroxy- 2-methylpropyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 337.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.89 (br. s, 1 H), 7.21 (d, J = 8.24 Hz, 1 H), 6.58 (dd, J = 8.70, 1.83Hz, 1 H), 6.51 (d, J = 1.83 Hz, 1 H), 5.87 (s, 1 H), 5.11-5.30 (m, 1 H),3.87 (s, 3 H), 3.84 (s, 3 H), 3.46-3.64 (m, 1 H), 1.11 (br. s., 3 H),0.96 (br. s., 3 H) 195

6-(2,4- dimethoxyphenyl)- 1-(3-hydroxy- 2-methylpropyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 337.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm10.07 (br. s., 1 H), 7.13 (d, J = 8.70 Hz, 1 H), 6.57 (dd, J = 8.70,2.29 Hz, 1 H), 6.52 (d, J = 2.29 Hz, 1 H), 5.87 (s, 1 H), 4.95 (br. s.,2 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.54 (dd, J = 11.91, 3.21 Hz, 1 H),3.34-3.41 (m, 1 H), 1.83 (br. s., 1 H), 0.62 (d, J = 6.87 Hz, 3 H) 196

6-(2,4- dimethoxyphenyl)- 1-(4- hydroxybutyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 337.1 ¹H NMR (400 MHz, METHANOL-d4) δ ppm7.20 (d, J = 8.20 Hz, 1 H), 6.66 (d, J = 2.15 Hz, 1 H), 6.64 (dd, J =8.20, 2.34 Hz, 1 H), 5.71 (s, 1 H), 4.44-4.56 (m, 1 H), 3.85 (s, 6 H),3.62-3.75 (m, 1 H), 3.32 (t, J = 6.64 Hz, 2 H), 1.66- 1.81 (m, 1 H),1.40-1.56 (m, 1 H), 1.16-1.32 (m, 2 H) 197

1-[(2R)-3- amino-2- hydroxypropyl]- 6-(2,4- dimethoxyphenyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one trifluoroacetate 338.0 1H NMR(400 MHz, DMSO-d6) δ ppm 12.72-12.82 (m, 1 H), 7.61-7.74 (m, 3 H),7.16-7.28 (m, 1 H), 6.59-6.75 (m, 2 H), 5.70-5.79 (m, 1 H), 5.60-5.65(m, 1 H), 4.53-4.63 (m, 1 H), 4.21-4.31 (m, 1 H), 3.77-3.86 (m, 6 H),2.72-2.85 (m, 2 H) 198

1-(2- aminoethyl)-2- thioxo-6-(2,4,5- trimethoxyphenyl)- 2,3-dihydropyrimidin- 4(1H)-one hydrochloride 338.1 1H NMR (400 MHz,DMSO-d6) δ ppm 12.79 (s, 1 H), 7.92 (br. s., 3 H), 6.99 (s, 1 H), 6.80(s, 1 H), 5.76 (d, J = 1.76 Hz, 1 H), 4.55 (dt, J = 13.96, 6.88 Hz, 1H), 3.93 (dt, J = 14.06, 7.03 Hz, 1 H), 3.84 (s, 3 H), 3.80 (s, 3 H),3.70 (s, 3 H), 2.80-2.97 (m, 2 H) 199

1-(3-amino-2- hydroxypropyl)- 6-(2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 338.1 1H NMR (400 MHz,DMSO-d6) δ ppm 12.69-12.76 (m, 1 H), 7.61-8.08 (m, 3 H), 7.13-7.26 (m, 1H), 6.56-6.71 (m, 2 H), 5.65-5.76 (m, 1 H), 5.60 (m, J = 4.90 Hz, 1 H),4.55 (s, 1 H), 4.15-4.30 (m, 1 H), 3.74-3.84 (m, 6 H), 3.54-3.63 (m, 1H), 2.61-2.95 (m, 2 H) 200

1-[(2S)-3-amino- 2- hydroxypropyl]- 6-(2,4- dimethoxyphenyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one trifluoroacetate 338.2 1H NMR(300 MHz, DMSO-d6) δ ppm 12.78 (m, 1 H), 7.63 (br. s, 3 H), 7.18-7.28(m, 1 H), 6.60-6.75 (m, 2 H), 5.71- 5.80(m, 1H), 5.58-5.66 (m, 1H),4.54-4.62 (m, 1H), 4.08- 4.23 (m, 1H), 3.78-3.85 (m, 6H), 3.23-3.41 (m,1H), 2.71- 2.83 (m, 1H), 2.38-2.45 (m, 1H) 201

1-(2,3- dihydroxypropyl)- 6-(2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 339.2 1H NMR (400 MHz, CHLOROFORM-d) δ ppm10.33 (br. s., 1 H) 7.17 (br. s., 1 H) 6.58 (br. s., 1 H) 6.52 (d, J =7.22 Hz, 1 H) 5.88 (d, J = 7.22 Hz, 1 H) 4.80-4.95 (m, 1 H) 4.60-4.73(m, 1 H) 3.99-4.14 (m, 1 H) 3.87 (s, 3 H) 3.83 (s, 3 H) 3.23-3.68 (m, 4H) 202

1-(2- hydroxyethyl)-2- thioxo-6-(2,4,5- trimethoxyphenyl)- 2,3-dihydropyrimidin- 4(1H)-one 339.2 1H NMR (500 MHz, DMSO-d6) δ ppm 12.68(s, 1 H), 6.95 (s, 1 H), 6.80 (s, 1 H), 5.74 (s, 1 H), 4.43-4.51 (m, 1H), 3.86 (s, 3 H), 3.82 (s, 3 H), 3.71 (s, 3 H), 3.64-3.70 (m, 1 H),3.49-3.56 (m, 1 H), 3.40-3.46 (m, 1 H) 203

1-[(2S)-2,3- dihydroxypropyl]- 6-(2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 339.2 1H NMR (400 MHz, CHLOROFORM-d) δ ppm10.33 (br. s., 1 H) 7.17 (br. s., 1 H) 6.58 (br. s., 1 H) 6.52 (d, J =7.22 Hz, 1 H) 5.88 (d, J = 7.22 Hz, 1 H) 4.80-4.95 (m, 1 H) 4.60-4.73(m, 1 H) 3.99-4.14 (m, 1 H) 3.87 (s, 3 H) 3.83 (s, 3 H) 3.23-3.68 (m, 4H) 204

1-[(2R)-2,3- dihydroxypropyl]- 6-(2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 339.2 1H NMR (400 MHz, CHLOROFORM-d) δ ppm10.33 (br. s., 1 H) 7.17 (br. s., 1 H) 6.58 (br. s., 1 H) 6.52 (d, J =7.22 Hz, 1 H) 5.88 (d, J = 7.22 Hz, 1 H) 4.80-4.95 (m, 1 H) 4.60-4.73(m, 1 H) 3.99-4.14 (m, 1 H) 3.87 (s, 3 H) 3.83 (s, 3 H) 3.23-3.68 (m, 4H) 205

2-[6-(4- methoxy-1- naphthyl)-4-oxo- 2-thioxo-3,4- dihydropyrimidin-1(2H)- yl]acetamide 342.2 1H NMR (400 MHz, DMSO-d6) δ ppm 12.90 (br. s,1 H), 8.25 (d, J = 7.33 Hz, 1 H), 7.69-7.77 (m, 1 H), 7.56-7.68 (m, 2H), 7.38-7.47 (m, 1 H), 7.23 (s, 1 H), 7.06 (d, J = 8.24 Hz, 1 H), 6.98(br. s., 1 H), 5.92 (d, J = 1.83 Hz, 1 H), 5.10-5.35 (m, 2 H), 4.02 (s,3 H) 206

6-(4-chloro-2,5- dimethoxyphenyl)- 1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 343 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.88 (br. s., 1 H), 7.03 (s, 1 H), 6.85 (s, 1 H), 5.84 (s, 1 H), 4.73(dt, J = 14.20, 5.15 Hz, 1 H), 3.91- 4.00 (m, 1 H), 3.87-3.90 (m, 1 H),3.86 (s, 3 H), 3.81 (s, 3 H), 3.59-3.73 (m, 1 H), 1.95 (br. s., 1 H) 207

6-(2,4- dimethoxyphenyl)- 1-(1H-pyrazol- 5-ylmethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 345.1 1H NMR (500 MHz, METHANOL-d4) δ ppm7.48 (br. s., 1 H), 6.90 (d, J = 8.05 Hz, 1 H), 6.62 (d, J = 2.20 Hz, 1H), 6.46 (d, J = 5.12 Hz, 1 H), 5.95- 6.13 (m, 2 H), 5.77 (s, 1 H),4.88-5.01 (m, 1 H), 3.82 (s, 3 H), 3.81 (s, 3 H) 208

2-{4-oxo-2- thioxo-6-[2- (trifluoromethoxy) phenyl]-3,4-dihydropyrimidin- 1(2H)- yl}acetamide 345.9 1H NMR (400 MHz, Methoanol-d3) d ppm 7.67 (ddd, J = 7.7, 7.6, 2.0 Hz, 1 H), 7.46-7.52 (m, 3 H),5.89 (s, 1 H), 5.50 (br. s., 1 H), 4.01 (br. s., 1H) 209

6-(2,4- dimethoxyphenyl)- 2-thioxo-1- (1H-1,2,4- triazol-5-ylmethyl)-2,3- dihydropyrimidin- 4(1H)-one 346.0 1.84 min WatersAtlantis dC18 5um 4.6x50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCNover 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05% TFA). Flowrate: 2 mL/min 210

1-(2- methoxyethyl)- 2-thioxo-6-[4- (trifluoromethoxy) phenyl]-2,3-dihydropyrimidin- 4(1H)-one 347.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.53 (br. s., 1 H), 7.42 (d, J = 8.70 Hz, 2 H), 7.34 (d, J = 8.24 Hz, 2H), 5.82 (d, J = 2.29 Hz, 1 H), 4.34 (br. s., 2 H), 3.67 (t, J = 5.27Hz, 2 H), 3.20 (s, 3 H) 211

6-(2,4- dimethoxyphenyl)- 1-(pyrrolidin- 2-ylmethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 348.4 1H NMR (400 MHz,DMSO-d6) δ ppm 12.89 (s, 1 H), 9.25 (br. s, 1 H), 8.08-8.71 (br. m., 1H), 7.24-7.42 (m, 1 H), 6.74 (d, J = 2.33 Hz, 1 H), 6.69 (dd, J = 8.61,2.09 Hz, 1 H), 5.80 (m, 1 H), 4.97-5.07 (m, 1 H), 3.81- 3.88 (m, 6 H),3.61-3.78 (m, 2 H), 2.96-3.17 (m, 2 H), 1.73- 1.90 (m, 1 H), 1.65 (m, 2H), 1.13-1.26 (m, 1 H) 212

6-(2,4- dimethoxyphenyl)- 1-(pyrrolidin- 3-ylmethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 348.4 1H NMR (300 MHz,DMSO-d6) δ ppm 12.80 (s, 1 H), 8.77 (br. s., 2 H), 7.27-7.38 (m, 1 H),6.73 (d, J = 2.09 Hz, 1 H), 6.67 (dd, J = 8.36, 2.09 Hz, 1 H), 5.76-5.79 (m, 1 H), 4.60-4.75 (m, 1 H), 3.84 (br. s., 4 H), 3.57 (s, 3 H),3.13-3.24 (m, 1 H), 3.01- 3.13 (m, 1 H), 2.85-2.97 (m, 1 H), 2.70-2.83(m, 1 H), 2.55- 2.69 (m, 1 H), 1.81-1.95 (m, 1 H), 1.62-1.79 (m, 1 H)213

6-(2,4- dimethoxyphenyl)- 1-[(2S)- tetrahydrofuran- 2-ylmethyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 349.1 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 9.59 (br. s, 1 H), 7.12-7.24 (m, 1 H), 6.56 (dd, J =8.24, 1.83 Hz, 1 H), 6.43-6.51 (m, 1 H), 5.75- 5.82 (m, 1 H), 4.67 (dd,J = 13.74, 2.29 Hz, 1 H), 4.53- 4.62 (m, 1 H), 3.85 (s, 3 H), 3.79-3.83(m, 3 H), 3.54 (q, J = 7.20 Hz, 1 H), 3.39 (dd, J = 13.28, 10.08 Hz, 1H), 3.15 (q, J = 7.17 Hz, 1 H), 1.89-2.02 (m, 1 H), 1.64-1.80 (m, 1 H),1.45-1.54 (m, 1 H), 1.23-1.35 (m, 1 H) 214

6-(2,4- dimethoxyphenyl)- 1-[(2R)- tetrahydrofuran- 2-ylmethyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 349.1 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.20- 7.28 (m, 1 H) 6.63-6.68 (m, 2 H) 5.70-5.74 (m,1 H) 4.71 (dd, J = 14.07, 2.74 Hz, 1 H) 4.56-4.65 (m, 1 H) 3.84-3.88 (m,6 H) 3.50-3.57 (m, 1 H) 3.43-3.50 (m, 1 H) 3.22 (dt, J = 8.26, 6.72 Hz,1 H) 1.93 (m, J = 12.46, 7.89, 7.89, 6.16 Hz, 1 H) 1.64-1.77 (m, 1 H)1.43- 1.55 (m, 1 H) 1.31-1.40 (m, 1 H) 215

N-{2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]ethyl}acetamide 350.1 1 1H NMR (400 MHz, DMSO-d6) δ ppm 12.70(br. s., 1 H), 7.77 (t, J = 5.95 Hz, 1 H), 7.20 (d, J = 8.24 Hz, 1 H),6.61-6.70 (m, 2 H), 5.70 (s, 1 H), 4.50 (dt, J = 13.40, 5.21 Hz, 1 H),3.82 (s, 3 H), 3.79 (s, 3 H), 3.59 (dt, J = 13.62, 6.70 Hz, 1 H), 3.15-3.28 (m, 2 H), 1.67 (s, 3 H) 216

3-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]-N- methylpropan- amide 350.1 1H NMR (400 MHz, DMSO-d6) δ ppm12.63 (br. s., 1 H), 7.71 (br. s., 1 H), 7.25 (d, J = 7.79 Hz, 1 H),6.70 (s, 1 H), 6.64 (d, J = 8.70 Hz, 1 H), 5.72 (s, 1 H), 4.37-4.53 (m,2 H), 3.83 (s, 3 H), 3.82 (s, 3 H), 3.35-3.44 (m, 2 H), 2.45 (d, J =4.58 Hz, 3 H) 217

3-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]-2- methylpropan- amide 350.2 1H NMR (500 MHz, DMSO-d6) δ ppm12.50-12.85 (m, 1 H) 7.15-7.34 (m, 2 H) 6.55-6.83 (m, 3 H) 5.64-5.77 (m,1 H) 4.34-4.67 (m, 1 H) 3.75-3.89 (m, 6 H) 3.46-3.71 (m, 1 H) 2.75-3.13(m, 1 H) 0.66-0.90 (m, 3 H) 218

1-(5- aminopentyl)-6- (2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 349.9 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.24 (d, J = 7.81 Hz, 1 H), 6.69 (s, 1 H), 6.66 (d, J= 8.00 Hz, 1 H), 5.75 (s, 1 H), 4.46-4.60 (m, 1 H), 3.87 (s, 6 H),3.62-3.75 (m, 1 H), 2.83 (br. s, 2 H), 1.69-1.83 (m, 1 H), 1.41-1.57 (m,3 H), 1.05-1.24 (m, 2 H) 219

1-(3-amino-3- methylbutyl)-6- (2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 350.1 1H NMR (400 MHz,DMSO-d6): δ 7.28 (d, 1 H), 6.71 (s, 1 H), 6.65 (d, 1 H), 5.76 (s, 1 H),4.49 (br. s., 1 H), 3.84 (s, 3 H), 3.82 (s, 3 H), 3.50-3.60 (br. s.,1H), 1.82-1.95 (m, 1 H), 1.42-1.55 (m, 1 H), 0.89 (s, 3 H), 0.80 (s, 3H): 220

6-(2,4- dimethoxyphenyl)- 1-[3- (dimethylamino) propyl]-2-thioxo- 2,3-dihydropyrimidin- 4(1H)-one 350.2 1H NMR (400 MHz, DMSO-d6) δ ppm 12.76(br. s., 1 H), 7.29 (d, J = 8.47 Hz, 1 H), 6.70 (d, J = 2.06 Hz, 1 H),6.64 (dd, J = 8.47, 2.06 Hz, 1 H), 5.74 (s, 1 H), 4.29-4.47 (m, 1 H),3.80 (s, 6 H), 3.50-3.68 (m, 1 H), 3.41-3.51 (m, 1 H), 2.74 (br. s., 1H), 2.55 (br. s., 6 H), 1.79- 1.94 (m, 1 H), 1.63-1.78 (m, 1 H) 221

ethyl [6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]acetate 351.2 1H NMR (400 MHz, DMSO-d6) δ ppm 12.94 (s, 1 H),7.11 (d, J = 8.70 Hz, 1 H), 6.70 (d, J = 2.29 Hz, 1 H), 6.63 (dd, J =8.24, 2.29 Hz, 1 H), 5.83 (s, 1 H), 5.18-5.40 (m, 1 H), 4.16- 4.31 (m, 1H), 4.02 (dtt, J = 10.88, 7.16, 7.16, 3.66, 3.66 Hz, 2 H), 3.82 (s, 6H), 1.08 (t, J = 7.10 Hz, 3 H) 222

2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]ethyl acetate 351.2 1H NMR (500 MHz, DMSO-d6) δ ppm 12.78 (br.s., 1 H) 7.28 (d, J = 8.54 Hz, 1 H) 6.70 (d, J = 2.20 Hz, 1 H) 6.67 (dd,J = 8.29, 2.20 Hz, 1 H) 5.75 (s, 1 H) 4.70 (dt, J = 14.70, 4.36 Hz, 1 H)4.29 (ddd, J = 11.95, 7.81, 4.39 Hz, 1 H) 4.02 (dt, J = 11.71, 4.64 Hz,1 H) 3.83 (s, 3 H) 3.82 (s, 3 H) 3.77-3.81 (m, 1 H) 1.91 (s, 3 H) 223

1-{2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]ethyl}urea 351.2 1.80 min Waters Atlantis dC18 5um 4.6x50 mm,95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95% MeCN to 5.0 min. (0.05% TFA). Flow rate: 2 mL/min 224

6-(2,4- dimethoxyphenyl)- 1-(3-hydroxy- 2,2- dimethylpropyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 351.1 1H NMR (400 MHz,METHANOL-d3) δ ppm 7.31 (d, J = 8.24 Hz, 1 H), 6.63-6.69 (m, 2 H), 5.76(s, 1 H), 5.19 (d, J = 15.11 Hz, 1 H), 3.87 (s, 3 H), 3.87 (s, 3 H),3.50 (d, J = 14.66 Hz, 1 H), 3.29 (d, J = 10.53 Hz, 1 H), 3.05 (d, J =10.99 Hz, 1 H), 0.83 (s, 3 H), 0.66 (s, 3 H) 225

6-(2,4- dimethoxyphenyl)- 1-(5- hydroxypentyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 351.1 ¹H NMR (500 MHz, METHANOL-d4) δ ppm7.22 (d, J = 8.29 Hz, 1 H), 6.68 (d, J = 1.95 Hz, 1 H), 6.66 (dd, J =8.29, 2.20 Hz, 1 H), 5.73 (s, 1 H), 4.44-4.57 (m, 1 H), 3.87 (s, 6 H),3.61-3.71 (m, 1 H), 3.40 (t, J = 6.46 Hz, 2 H), 1.68- 1.79 (m, 1 H),1.39-1.51 (m, 1 H), 1.25-1.36 (m, 2 H), 1.03- 1.20 (m, 2 H) 226

6-(2,4- dimethoxyphenyl)- 1-(2- isopropoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 351.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.58 (br. s., 1 H) 7.15 (d, J = 8.40 Hz, 1 H) 6.55 (dd, J = 8.40, 2.35Hz, 1 H) 6.50 (d, J = 2.35 Hz, 1 H) 5.79 (d, J = 2.35 Hz, 1 H) 4.64-4.71 (m, 1 H) 3.87 (s, 3 H) 3.82 (s, 3 H) 3.69-3.81 (m, 2 H) 3.49 (ddd,J = 9.58, 5.86, 3.13 Hz, 1 H) 3.46 (dt, J = 12.31, 6.25 Hz, 1 H) 1.04(dd, J = 6.06, 1.37 Hz, 6 H) 227

6-(2,4- dimethoxyphenyl)- 1-[3- (methylthio)prop- yl]-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 353.1 1H NMR (400 MHz, DMSO-d6) d ppm 7.32(d, J = 8.4 Hz, 1 H), 6.73 (d, J = 2.0 Hz, 1 H), 6.68 (dd, J = 8.4, 2.0Hz, 1 H), 5.76 (d, J = 2.0 Hz, 1 H), 4.45 (br. s., 1 H), 3.84 (s, 6H),3.70 (br. s., 1 H), 2.22 (tt, d = 6.4, 6.4 Hz, 2 H), 1.85-1.91 (m, 1 H),1.83 (s, 3 H), 1.59-1.65 (m, 1 H) 228

1-benzyl-6-(2,4- dimethoxyphenyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 355.2 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.84 (br. s., 1 H),7.14-7.22 (m, 3 H), 6.84-6.93 (m, 2 H), 6.72 (d, J = 8.24 Hz, 1 H), 6.44(d, J = 1.83 Hz, 1 H), 6.34 (dd, J = 8.47, 2.06 Hz, 1 H), 5.96 (d, J =16.03 Hz, 1 H), 5.84 (s, 1 H), 4.94 (d, J = 15.11 Hz, 1 H), 3.82 (s, 3H), 3.70 (s, 3 H) 229

2-[6-(4-chloro- 2,5- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]acetamide 356.1 1H NMR (400 MHz,METHANOL-d3) δ ppm 7.20 (s, 1 H), 6.96 (s, 1 H), 5.84 (s, 1 H), 4.65(br. s, 2 H), 3.83 (s, 3 H), 3.81 (s, 3 H) 230

6-(2,4- dimethoxyphenyl)- 1-(pyridin-2- ylmethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 356.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.57 (br. s., 1 H), 8.43 (dd, J = 4.58, 0.90 Hz, 1 H), 7.57 (ddd, J =7.60, 7.60, 1.80 Hz, 1 H), 7.11 (ddd, J = 7.79, 5.04, 0.92 Hz, 1 H),7.00 (d, J = 7.79 Hz, 1 H), 6.88 (d, J = 8.24 Hz, 1 H), 6.43 (d, J =2.29 Hz, 1 H), 6.32 (dd, J = 8.24, 2.29 Hz, 1 H), 6.02 (d, J = 16.03 Hz,1 H), 5.87 (s, 1 H), 4.95 (d, J = 16.49 Hz, 1 H), 3.79 (s, 3 H), 3.75(s, 3 H) 231

6-(2,4- dimethoxyphenyl)- 1-(pyridin-3- ylmethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 356.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.56 (br. s., 1 H), 8.46 (dd, J = 4.81, 1.60 Hz, 1 H), 7.97 (d, J = 1.83Hz, 1 H), 7.51 (ddd, J = 8.00, 1.80, 1.80 Hz, 1 H), 7.18 (ddd, J = 8.01,4.81, 0.92 Hz, 1 H), 6.79 (d, J = 8.24 Hz, 1 H), 6.46 (d, J = 2.29 Hz, 1H), 6.42 (dd, J = 8.24, 2.29 Hz, 1 H), 5.88 (d, J = 15.11 Hz, 1 H), 5.84(s, 1 H), 5.06 (d, J = 15.57 Hz, 1 H), 3.84 (s, 3 H), 3.68 (s, 3 H) 232

6-(2,4- dimethoxyphenyl)- 1-(pyridin-4- ylmethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 356.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm11.02 (br. s, 1 H), 8.48 (d, J = 5.95 Hz, 2 H), 6.87 (d, J = 5.95 Hz, 2H), 6.77 (d, J = 8.24 Hz, 1 H), 6.42 (d, J = 2.29 Hz, 1 H), 6.36 (dd, J= 8.24, 2.29 Hz, 1 H), 5.88- 5.90 (m, 1 H), 5.87 (s, 1 H), 4.93-5.08 (m,1 H), 3.81 (s, 3 H), 3.66 (s, 3 H) 233

6-(4-chloro-2,5- dimethoxyphenyl)- 1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 357.1 1H NMR (400 MHz, DMSO-d6) δ ppm 12.81(br. s., 1 H), 7.27 (s, 1 H), 7.16 (s, 1 H), 5.83 (s, 1 H), 4.50 (dt, J= 14.14, 5.41 Hz, 1 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.66-3.75 (m, 1H), 3.52 (dt, J = 9.96, 6.93 Hz, 1 H), 3.33- 3.39 (m, 1 H), 3.01 (s, 3H) 234

6-(2,4- dimethoxyphenyl)- 1-(pyrimidin-2- ylmethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 357.0 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.81 (br. s., 1 H), 8.59 (d, J = 4.81 Hz, 2 H), 7.12 (t, J = 4.81 Hz, 1H), 6.91 (d, J = 8.47 Hz, 1 H), 6.44 (d, J = 1.83 Hz, 1 H), 6.28 (dd, J= 8.36, 1.95 Hz, 1 H), 6.21 (d, J = 17.40 Hz, 1 H), 5.87 (s, 1 H), 4.94(d, J = 17.17 Hz, 1 H), 3.81 (s, 3 H), 3.76 (s, 3 H) 235

6-(2,4- dimethoxyphenyl)- 1-(piperidin-4- ylmethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 362.1 1H NMR (400 MHz,DMSO-d6) δ ppm 12.77 (d, J = 1.86 Hz, 1 H), 8.66-8.77 (m, 1 H),8.17-6-(2,4- 8.31 (m, 1 H), 7.32 (d, J = 8.37 Hz, 1 H), 6.71 (d, J =2.33 Hz, 1 H), 6.67 (dd, J = 8.37, 2.33 Hz, 1 H), 5.76 (d, J = 2.33 Hz,1 H), 4.51-4.77 (m, 1 H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.67-3.79 (m, 1H), 3.03-3.20 (m, 2 H), 2.57- 2.80 (m, 2 H), 1.98-2.16 (m, 1 H),1.56-1.71 (m, 1 H), 1.38- 1.52 (m, 1 H), 1.11-1.27 (m, 1 H), 0.78-0.99(m, 1 H) 236

N- [amino(imino) methyl]-2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl]acetamide trifluoroacetate 364.01H NMR (400 MHz, METHANOL-d4) δ ppm 7.19 (d, J = 8.41 Hz, 1 H), 6.68 (d,J = 2.15 Hz, 1 H), 6.63 (dd, J = 8.41, 2.35 Hz, 1 H), 5.84 (s, 1 H),5.44 (br. d, J = 15.10 Hz, 1 H), 4.55 (br. d, J = 17.40 Hz, 1 H), 3.88(s, 3 H), 3.85 (s, 3 H) 237

3-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]-N,N- dimethylpropan- amide 364.1 1H NMR (400 MHz, DMSO-d6) δppm 12.71 (br. s, 1 H), 7.30 (d, J = 8.24 Hz, 1 H), 6.70 (d, J = 1.83Hz, 1 H), 6.65 (dd, J = 8.24, 2.29 Hz, 1 H), 5.74 (s, 1 H), 4.39-4.55(m, 2 H), 3.82 (s, 6 H), 2.81 (s, 3 H), 2.69 (s, 3 H) 238

6-(2,4- dimethoxyphenyl)- 1-(morpholin- 2-ylmethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 364.2 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.19 (d, J = 8.39 Hz, 1 H), 6.57-6.69 (m, 2 H), 5.73(s, 1 H), 4.74 (dd, J = 14.45, 2.15 Hz, 1 H), 4.33 (ddt, J = 11.18,8.44, 2.39 Hz, 1 H), 3.93 (dd, J = 12.98, 3.61 Hz, 1 H), 3.84 (d, J =1.17 Hz, 6 H), 3.54-3.68 (m, 3 H), 3.13 (d, J = 12.69 Hz, 1 H), 2.95(td, J = 12.69, 3.90 Hz, 1 H), 2.67 (t, J = 11.91 Hz, 1 H) 239

ethyl 2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]propanoate 365.1 1H NMR (400 MHz, DMSO-d6) δppm 12.69-12.78 (m, 1 H), 7.09-7.31 (m, 1 H), 6.61-6.73 (m, 2 H),5.75-5.83 (m, 1 H), 4.44-4.57 (m, 1 H), 3.91-4.18 (m, 2 H), 3.75-3.85(m, 6 H), 1.67 (d, J = 6.90 Hz, 3 H), 1.09- 1.24 (m, 3 H) 240

ethyl 3-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]propanoate 365.1 1H NMR (400 MHz, DMSO-d6) δppm 12.78 (s, 1 H), 7.29 (d, J = 8.24 Hz, 1 H), 6.71 (d, J = 1.83 Hz, 1H), 6.66 (dd, J = 8.24, 2.29 Hz, 1 H), 5.75 (d, J = 2.29 Hz, 1 H),4.43-4.58 (m, 1 H), 3.94 (q, J = 6.87 Hz, 2 H), 3.83-3.89 (m, 1 H), 3.82(s, 3 H), 3.82 (s, 3 H), 2.59 (td, J = 10.19, 6.18 Hz, 2 H), 1.08 (t, J= 7.10 Hz, 3 H) 241

N-(2- aminoethyl)-2- [6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]acetamide hydrochloride 364.8 1HNMR (400MHz, METHANOL-d4): δ 8.28 (m, 1H), 7.15 (d, 1H), 6.66 (d, 1H), 6.62 (dd,1H), 5.79 (s, 1H), 5.42-5.40 (m, 1H), 4.37-4.23 (m, 1H), 3.90 (s, 3H),3.80 (s, 3H), 3.20-3.15 (m, 1H), 3.05- 3.12 (m, 1H), 2.95-2.85 (m, 2H).242

N~2~-{2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]ethyl}glycin- amide 365.1 1HNMR (400 MHz,METHANOL-d4): δ 7.14 (d, 1H), 6.55-6.60 (m, 2H), 5.65 (s, 1H), 4.55-4.62(m, 1H), 4.51 (s, 1H), 3.77 (s, 6H), 3.00 (s, 2H), 2.64-2.79 (m, 2H).243

N-{2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]ethyl}glycine hydrochloride 365.9 1H NMR (400 MHz, DMSO-d6): δ12.88 (br, 1H), 7.26 (d, 1H), 6.66-6.74 (m, 2H), 5.78 (s,1H), 4.76(m,1H), 3.92 (m, 1H), 3.83 (s, 6H), 3.70 (s, 2H), 3.02 (m, 2H). 244

2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]ethyl glycinate tosylate 366.2 1H NMR (400 MHz, CD₃OD) δ 2.37(s, 3 H), 3.71 (d, J = 17.2 Hz, 1 H), 3.79 (d, J = 17.2 Hz, 1 H), 3.87(s, 3 H), 3.88 (s, 3 H), 4.04 (ddd, J = 14.8, 6.8, 5.5 Hz, 1 H), 4.28(dt, J = 11.7, 5.3 Hz, 1 H), 4.51 (ddd, J = 11.6, 6.7, 5.1 Hz, 1 H),4.97 (dt, J = 14.5, 5.0 Hz, 1 H), 5.78 (s, 1 H), 6.65- 6.72 (m, 2 H),7.23 (d, J = 8.0 Hz, 2 H), 7.27 (d, J = 8.0 Hz, 1 H), 7.71 (d, J = 8.2Hz, 2 H) 245

6-(2,4- dimethoxyphenyl)- 1-{3-[(2- hydroxyethyl) amino]propyl}-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 365.9 1.58 min Waters AtlantisdC18 5um 4.6x50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05% TFA). Flow rate: 2mL/min 246

{2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]ethoxy}acetic acid 388.9 [M + Na]+ 1HNMR (400 MHz,METHANOL-d4): δ 7.25 (d, 1H), 6.64 (m, 2H), 5.73 (s, 1H), 4.74 (m, 1H),3.92 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.75 (m, 3H), 3.61 (m, 1H).247

6-(2,4- dimethoxyphenyl)- 1-[(5- methylpyrazin- 2-yl)methyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 371.1 1H NMR (400 MHz, DMSO-d6)δ ppm 12.81 (br. s., 1 H), 8.34 (s, 1 H), 8.19 (s, 1 H), 6.98 (d, J =8.24 Hz, 1 H), 6.58 (d, J = 2.06 Hz, 1 H), 6.42 (dd, J = 8.36, 2.18 Hz,1 H), 5.81 (d, J = 16.26 Hz, 1 H), 5.78 (s, 1 H), 4.88 (d, J = 16.72 Hz,1 H), 3.72 (s, 3 H), 3.71 (br. s., 3 H), 2.39 (s, 3 H) 248

2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]ethanesulfon- amide 372.0 1H NMR (400 MHz, DMSO-d6) δ ppm12.76 (br. s., 1 H), 7.26 (d, J = 8.24 Hz, 1 H), 6.92 (s, 2 H), 6.66 (d,J = 2.06 Hz, 1 H), 6.61 (dd, J = 8.47, 2.06 Hz, 1 H), 5.72 (d, J = 1.60Hz, 1 H), 4.57 (br. s., 1 H), 3.92-4.06 (m, 1 H), 3.79 (s, 3 H), 3.78(s, 3 H), 3.08-3.29 (m, 2 H) 249

6-(2,4- dimethoxyphenyl)- 1-[2-(1H- imidazol-2- ylamino)ethyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 374.0 1H NMR (500 MHz,METHANOL-d4) δ ppm 7.05 (d, J = 8.29 Hz, 1 H) 6.71 (s, 2 H) 6.62 (d, J =2.20 Hz, 1 H) 6.43 (dd, J = 8.42, 2.07 Hz, 1 H) 5.77 (s, 1 H) 4.84 (br.s., 1 H) 3.90- 3.93 (m, 1 H) 3.88 (s, 3 H) 3.84 (s, 3 H) 3.26-3.33 (m, 2H) 250

1-[2-(4,5- dihydro-1H- imidazol-2- ylamino)ethyl]- 6-(2,4-dimethoxyphenyl)- 2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 376.1 1H NMR(400 MHz, METHANOL-d4) δ ppm 7.21 (d, J = 8.00 Hz, 1 H), 6.68-6.73 (m, 2H), 5.79 (s, 1 H), 4.72-4.84 (m, 2 H), 3.89 (s, 6 H), 3.69- 3.81 (m, 1H), 3.57-3.67 (m, 2 H), 3.43-3.57 (m, 2 H), 3.23 (d, J = 15.23 Hz, 1 H)251

6-(2,4- dimethoxyphenyl)- 1-(2- morpholin-4- ylethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 377.8 1HNMR (400 MHz, CDCl3): δ 9.89 (br.s., 1H), 7.13 (d, 1H), 6.56 (dd, 1H), 6.53 (s, 1H), 5.80 (s, 1H), 4.68(br. s., 1H), 3.81- 3.85 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.58-3.65(m, 4H), 2.52-2.66 (m, 2H), 2.28-2.38 (m, 4H). 252

6-(2,4- dimethoxyphenyl)- 1-[(4- hydroxypiperidin- 4-yl)methyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one hydrochloride 378.1 1H NMR (500MHz, DMSO-d6) δ ppm 12.73 (br. s., 1 H), 8.63 (d, J = 8.78 Hz, 1 H),8.26 (d, J = 10.00 Hz, 1 H), 7.25 (d, J = 8.29 Hz, 1 H), 6.66 (s, 1 H),6.63 (d, J = 8.29 Hz, 1 H), 5.74 (d, J = 1.46 Hz, 1 H), 5.24 (d, J =14.64 Hz, 1 H), 4.82 (br. s., 1 H), 3.82 (s, 3 H), 3.81 (s, 3 H),3.47-3.53 (m, 1 H), 3.05 (d, J = 11.95 Hz, 1 H), 2.97 (d, J = 11.22 Hz,1 H), 2.86 (q, J = 11.63 Hz, 2 H), 1.88 (td, J = 13.54, 3.90 Hz, 1 H),1.55 (d, J = 13.91 Hz, 1 H), 1.48 (td, J = 13.42, 4.15 Hz, 1 H), 1.29(d, J = 13.42 Hz, 1 H) 253

1-{4-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]butyl}guanidine 378.0 1HNMR (400 MHz, METHANOL-d4): δ 8.57(br, 1H), 7.25 (d, 1H), 6.71 (d, 1H), 6.68 (dd, 1H), 5.77 (s, 1H),4.58-4.61 (m, 1H), 3.70-3.72 (m, 1H), 3.02-3.06 (t, 2H), 1.76- 1.78 (m,1H), 1.52-1.55 (m, 1H), 1.33-1.40 (m, 2H). 254

N~2~-{[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]acetyl}glycin- amide 305.1 [M − NHCH2CONH2]+ 1H NMR (400 MHz,CD₃OD) δ 3.69 (d, J = 17.0 Hz, 1 H), 3.79 (d, J = 17.0 Hz, 1 H), 3.85(s, 3 H), 3.86 (s, 3 H), 4.34 (br. d, J = 16.2 Hz, 1 H), 5.33 (br. d, J= 14.9 Hz, 1 H), 5.81 (s, 1 H), 6.61 (dd, J = 8.5, 2.2 Hz, 1 H), 6.66(d, J = 2.3 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 1 H) 255

N-{2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3, 4- dihydropyrimidin-1(2H)-yl]ethyl}- D-alaninamide trifluoroacetate 379.2 7.51 min ChiralcelOD-H 4.6 mmx25 cm, 75% CO2/25% MeOH (0.2% iPrNH2). Flow rate: 2.5 mL/min256

N-{2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]ethyl}- L-alaninamide trifluoroacetate 379.2 6.32 min ChiralcelOD-H 4.6 mmx25 cm, 75% CO2/25% MeOH (0.2% iPrNH2). Flow rate: 2.5 mL/min257

N-{2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]ethyl}methane sulfonamide 386.1 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 9.48 (br. s., 1 H), 7.21 (d, J = 8.70 Hz, 1 H), 6.61 (dd, J =8.24, 2.29 Hz, 1 H), 6.54 (d, J = 2.29 Hz, 1 H), 5.85 (d, J = 2.29 Hz, 1H), 4.62 (t, J = 6.64 Hz, 2 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.27-3.47(m, 2 H), 2.86 (s, 3 H) 258

2-{[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]methyl} pyrrolidine-1- carboximidamide trifluoroacetate 390.11.72 min Waters Atlantis dC18 5um 4.6x50 mm, 95% H2O/5% MeCN linear to5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05%TFA). Flow rate: 2 mL/min 259

3-{[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]methyl} pyrrolidine-1- carboximidamide trifluoroacetate 390.11.69 min Waters Atlantis dC18 5um 4.6x50 mm, 95% H2O/5% MeCN linear to5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05%TFA). Flow rate: 2 mL/min 260

6-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]norleucinamide hydrochloride 393.1 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.23 (d, J = 8.20 Hz, 1 H), 6.68 (d, J = 2.15 Hz, 1H), 6.66 (dd, J = 8.39, 2.54 Hz, 1 H), 5.75 (s, 1 H), 4.48-4.59 (m, 1H), 3.87 (s, 6 H), 3.75-3.81 (m, 1 H), 3.65-3.74 (m, 1 H), 1.73-1.83 (m,1 H), 1.63-1.73 (m, 2 H), 1.45-1.57 (m, 1 H), 1.14-1.25 (m, 2 H) 261

3-{[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]methyl}-1H- pyrazole-1- carbothioamide 404.2 1H NMR (500 MHz,DMSO-d6) δ ppm 12.81 (d, J = 1.71 Hz, 1 H), 9.86 (s, 1 H), 9.11 (s, 1H), 8.47 (d, J = 2.93 Hz, 1 H), 7.20 (d, J = 8.54 Hz, 1 H), 6.63 (d, J =2.20 Hz, 1 H), 6.51 (dd, J = 8.29, 2.20 Hz, 1 H), 6.32 (d, J = 2.93 Hz,1 H), 5.80 (d, J = 2.20 Hz, 1 H), 5.77 (d, J = 17.08 Hz, 1 H), 4.78 (d,J = 16.34 Hz, 1 H), 3.77 (s, 3 H), 3.75 (s, 3 H) 262

6-(2,4- dimethoxyphenyl)- 1-[(1- glycylpyrrolidin- 2-yl)methyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one hydrochloride 405.1 0.83 minColumn: Xtimate C18, 2.1x30 mm, 3 μm; Mobile phase: from 10% MeCN (0.06%TFA) in water (0.06% TFA) to 80% MeCN (0.06% TFA) in water (0.06% TFA);wavelength; 220 nm 263

N-{2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]ethyl}- L-valinamide trifluoroacetate 407.3 5.74 min Column:XBRIDGE- C18 4.6 mmX150 mm 5 μm Mobile phase-A = 0.1% TFA IN MeCN, B =0.1% TFA IN WATER: Phase A = 5% to 1.5 min, linear to 100% to 10 min.Flow rate = 1.5 mL/min. 264

1-(2- aminoethyl)-6- (3- methoxyphenyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one hydrochloride 278.1 1H NMR (300 MHz, DMSO-d6) δ ppm 12.87 (br.s., 1 H), 7.81 (br. s., 3 H), 7.46 (t, J = 7.67 Hz, 1 H), 7.10-7.17 (m,2 H), 7.07 (d, J = 7.67 Hz, 1 H), 5.82 (s, 1 H), 4.31 (t, J = 6.62 Hz, 2H), 3.81 (s, 3 H), 2.90-3.01 (m, 2 H) 265

1-(3- aminopropyl)-6- (3- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 292.0 1H NMR (400 MHz,DMSO-d6) δ ppm 12.80 (s, 1 H), 7.73 (br. s, 3 H), 7.45 (dd, J = 9.05,7.58 Hz, 1 H), 7.09-7.13 (m, 2 H), 7.07 (d, J = 7.83 Hz, 1 H), 5.82 (d,J = 1.96 Hz, 1 H), 4.02-4.14 (m, 2 H), 3.81 (s, 3 H), 2.53- 2.59 (m, 2H), 1.79-1.90 (m, 2 H) 266

1-allyl-6-(2,4- dimethoxyphenyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 305.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.35 (br. s., 1H), 7.04 (d, J = 8.19 Hz, 1 H), 6.52 (d, J = 2.34 Hz, 1 H), 6.47-6.50(m, 1 H), 5.82 (d, J = 2.15 Hz, 1 H), 5.72 (ddt, J = 16.78, 10.93, 5.46,5.46 Hz, 1 H), 5.21 (dd, J = 15.80, 5.07 Hz, 1 H), 5.04 (dd, J = 10.34,0.98 Hz, 1 H), 4.77 (dd, J = 17.27, 0.88 Hz, 1 H), 4.24 (dd, J = 15.80,6.05 Hz, 1 H), 3.84 (s, 3 H), 3.79 (s, 3 H) 267

6-(2,4- dimethoxyphenyl)- 1-[(2R)- pyrrolidin-2- ylmethyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one hydrochloride 348.1 1H NMR (500MHz, DMSO-d6) δ ppm 12.89 (br. s., 1 H), 9.25- 9.43 (m, 1 H), 8.74 (br.s., 1 H), 7.25-7.43 (m, 1 H), 6.73 (d, J = 1.46 Hz, 1 H), 6.68 (dd, J =8.42, 1.83 Hz, 1 H), 5.73- 5.85 (m, 1 H), 4.96-5.08 (m, 1 H), 3.80-3.88(m, 6 H), 3.61- 3.77 (m, 1 H), 3.42-3.53 (m, 1 H), 2.93-3.15 (m, 2 H),1.73- 1.90 (m, 1 H), 1.50-1.73 (m, 2 H), 1.14-1.25 (m, 1 H) 268

6-(2,4- dimethoxyphenyl)- 1-[(2S)- pyrrolidin-2- ylmethyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one hydrochloride hydrochloridehydrochloride 348.1 1H NMR (500 MHz, DMSO-d6) δ ppm 12.89 (br. s., 1 H),9.25- 9.43 (m, 1 H), 8.74 (br. s., 1 H), 7.25-7.43 (m, 1 H), 6.73 (d, J= 1.46 Hz, 1 H), 6.68 (dd, J = 8.42, 1.83 Hz, 1 H), 5.73- 5.85 (m, 1 H),4.96-5.08 (m, 1 H), 3.80-3.88 (m, 6 H), 3.61- 3.77 (m, 1 H), 3.42-3.53(m, 1 H), 2.93-3.15 (m, 2 H), 1.73- 1.90 (m, 1 H), 1.50-1.73 (m, 2 H),1.14-1.25 (m, 1 H) 269

1-[2-(2- aminoethoxy) ethyl]-6-(2,4- dimethoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one hydrochloride 352.3 1H NMR (300 MHz,DMSO-d6) δ ppm 12.78 (br. s, 1 H), 7.73 (br. s, 3 H), 7.29 (d, J = 8.36Hz, 1 H), 6.72 (s, 1 H), 6.66 (dd, J = 8.36, 2.09 Hz, 1 H), 5.76 (d, J =2.09 Hz, 1 H), 4.55-4.68 (m, 1 H), 3.83 (s, 6 H), 3.70-3.79 (m, 1 H),3.47-3.56 (m, 2 H), 3.34-3.41 (m, 2 H), 2.80-2.90 (m, 2 H) 270

2-{3-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]propyl}guanidine trifluoroacetate 364.1 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.22 (d, J = 8.41 Hz, 1 H), 6.68 (d, J = 1.96 Hz, 1H), 6.65 (dd, J = 8.41, 2.15 Hz, 1 H), 5.76 (s, 1 H), 4.51-4.63 (m, 1H), 3.86 (s, 6 H), 3.75-3.83 (m, 1 H), 2.98-3.09 (m, 2 H), 1.86-2.00 (m,1 H), 1.67-1.79 (m, 1 H)

The following Examples of Table 4 were prepared from the correspondingaryl halide to afford the intermediate beta-keto-ester as describedabove for the Preparations in the Aryl Halide Route section followed byemploying the methods described in the I. Beta Keto Ester Route Sectionas well as standard methods and techniques known to those skilled in theart.

TABLE 4 Examples from Aryl Halide Route Ex- 1H NMR Spectral Data orample Obs HPLC Retention Time # Structure Compound Name Mass andConditions 271

1-(2-hydroxyethyl)-6- [2-(2- methoxyethyl)phenyl]- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 306.9 1H NMR (500 MHz, CHLOROFORM-d) δ ppm10.31 (br. s., 1 H), 7.48 (dd, J = 7.80, 7.80 Hz, 1 H), 7.42 (d, J =7.81 Hz, 1 H), 7.35 (dd, J = 7.60 Hz, 1 H), 7.25 (d, J = 7.81 Hz, 1 H),5.88 (s, 1 H), 4.57 (dt, J = 13.80, 5.80 Hz, 1 H), 3.92 (dt, J = 14.00,5.90 Hz, 1 H), 3.75-3.85 (m, 2 H), 3.61 (t, J = 6.46 Hz, 2 H), 3.31 (s,3 H), 2.88 (dt, J = 14.45, 7.04 Hz, 1 H), 2.73 (dt, J = 14.45, 5.95 Hz,1 H) 272

2-{2-[3-(2- aminoethyl)-6-oxo-2- thioxo-1,2,3,6- tetrahydropyrimidin-4-yl]phenoxy}acetamide trifluoroacetate 320.9 1H NMR (500 MHz,METHANOL-d4) δ ppm 3.11-3.20 (m, 1 H) 3.26- 3.33 (m, 1 H) 4.46 (dt, J =13.72, 6.92 Hz, 1 H) 4.65 (d, J = 6.10 Hz, 1 H) 4.70-4.81 (m, 2 H) 5.89(s, 1 H) 7.08 (d, J = 8.54 Hz, 1 H) 7.19 (t, J = 7.56 Hz, 1 H) 7.40 (dd,J = 7.32, 1.22 Hz, 1 H) 7.54-7.60 (m, 1 H) 273

6-(2,5-dimethoxy-4- methylphenyl)-1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 323.2 1H NMR (500 MHz, METHANOL-d4) δ ppm6.97 (s, 1 H), 6.88 (s, 1 H), 5.78 (s, 1 H), 4.61- 4.71 (m, 1 H),3.85-3.91 (m, 1 H), 3.84 (s, 3 H), 3.82 (s, 3 H), 3.79-3.81 (m, 1 H),3.59-3.67 (m, 1 H), 2.28 (s, 3 H) 274

1-(2-hydroxyethyl)-6- (4-methoxy-1- naphthyl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 329.0 2.53 min Waters Atlantis dC18 5 um4.6 × 50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min,HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05% TFA). Flow rate: 2 mL/min 275

6-(2,5-dimethoxy-4- methylphenyl)-1-(2- methoxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 337.1 2.79 min Waters Atlantis dC18 5 um 4.6× 50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at5% H2O/95% MeCN to 5.0 min. (0.05% TFA). Flow rate: 2 mL/min

The following Examples of Table 5 were prepared from6-iodo-1-(2-methoxyethyl)-2-(methylthio)pyrimidin-4(1H)-one and theappropriate aryl boronate as described above for the Preparations andprocedures in the Suzuki Route section as well as standard methods andtechniques known to those skilled in the art.

TABLE 5 Examples from Suzuki Route Ex- 1H NMR Spectral Data or ampleCompound Obs HPLC Retention Time and # Structure Name Mass Conditions276

1-(2- methoxyethyl)- 6-(2-naphthyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 313.1 1H NMR (400 MHz, METHANOL-d3) δ ppm 7.93- 8.05 (m, 4 H),7.58-7.65 (m, 2 H), 7.52 (dd, J = 8.24, 1.83 Hz, 1 H), 5.90 (s, 1 H),4.40-4.52 (m, 2 H), 3.59-3.68 (m, 2 H), 3.07 (s, 3 H) 277

6-(2-furyl)-1-(2- methoxyethyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 253.1 1H NMR (400 MHz, METHANOL-d3) δ ppm 7.80 (dd, J = 1.83,0.92 Hz, 1 H), 7.06 (dd, J = 3.66, 0.92 Hz, 1 H), 6.66 (dd, J = 3.21,1.83 Hz, 1 H), 6.10 (s, 1 H), 4.66 (t, J = 5.04 Hz, 2 H), 3.73 (t, J =6.18 Hz, 2 H), 3.25 (s, 3 H) 278

1-(2- methoxyethyl)- 6-(1H-pyrazol-5- yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 253.1 1H NMR (400 MHz, METHANOL-d3) δ ppm7.81 (br. s., 1 H), 6.66 (d, J = 2.29 Hz, 1 H), 5.99 (s, 1 H), 4.76 (br.s., 2 H), 3.66 (t, J = 6.18 Hz, 2 H), 3.17 (s, 3 H) 279

1-(2- methoxyethyl)- 6-pyridin-3-yl-2- thioxo-2,3- dihydropyrimidin-4(1H)-one 264.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.76 (br. s., 1 H),8.76 (dd, J = 4.81, 1.60 Hz, 1 H), 8.64 (d, J = 1.83 Hz, 1 H), 7.72(ddd, J = 7.80, 2.10, 2.10 Hz, 1 H), 7.45 (ddd, J = 7.79, 4.58, 0.92 Hz,1 H), 5.85 (s, 1 H), 4.34 (br. s., 2 H), 3.67 (t, J = 5.04 Hz, 2 H),3.21 (s, 3 H) 280

3-(2- methoxyethyl)- 2-thioxo-2,3- dihydro-4,5′- bipyrimidin- 6(1H)-one265.1 1H NMR (400 MHz, METHANOL-d3) δ ppm 9.26 (s, 1 H), 8.90 (s, 2 H),5.94 (s, 1 H), 4.35 (br. s., 2 H), 3.67 (t, J = 4.81 Hz, 2 H), 3.20 (s,3 H) 281

1-(2- methoxyethyl)- 6-(1-methyl-1H- pyrrol-2-yl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 266.1 1H NMR (400 MHz, METHANOL-d3) δ ppm6.87 (dd, J = 2.70, 1.80 Hz, 1 H), 6.32 (dd, J = 3.66, 1.83 Hz, 1 H),6.19 (dd, J = 3.66, 2.75 Hz, 1 H), 5.86 (s, 1 H), 4.50 (br. s., 2 H),3.62 (t, J = 5.27 Hz, 2 H), 3.58 (s, 3 H), 3.12 (s, 3 H) 282

1-(2- methoxyethyl)- 6-(2-thienyl)-2- thioxo-2,3- dihydropyrimidin-4(1H)-one 269.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.54 (br. s., 1 H),7.53 (dd, J = 5.04, 1.37 Hz, 1 H), 7.33 (dd, J = 3.66, 0.92 Hz, 1 H),7.13 (dd, J = 5.04, 3.66 Hz, 1 H), 6.02 (d, J = 2.29 Hz, 1 H), 4.53 (t,J = 5.72 Hz, 2H), 3.74 (t, J = 5.72 Hz, 2 H), 3.28 (s, 3 H) 283

1-(2- methoxyethyl)- 6-(3- methylphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 277.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.55 (br. s., 1 H), 7.29-7.41 (m, 2 H), 7.12-7.16 (m, 2 H), 5.83 (d, J =2.75 Hz, 1 H), 4.38 (t, J = 5.27 Hz, 2 H), 3.63 (t, J = 5.50 Hz, 2 H),3.18 (s, 3 H), 2.42 (s, 3 H) 284

1-(2- methoxyethyl)- 6-(2- methylphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 277.2 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.65 (br. s., 1 H), 7.41 (ddd, J = 7.80, 7.80, 1.80 Hz, 1 H), 7.28-7.34(m, 2 H), 7.23 (dd, J = 6.87, 1.83 Hz, 1 H), 5.82 (d, J = 2.29 Hz, 1 H),4.57 (dt, J = 13.74, 5.04 Hz, 1 H), 3.89 (dt, J = 13.28, 6.87 Hz, 1 H),3.67 (ddd, J = 10.53, 7.33, 5.04 Hz, 1 H), 3.56 (dt, J = 10.53, 5.04 Hz,1 H), 3.16 (s, 3 H), 2.25 (s, 3 H) 285

1-(2- methoxyethyl)- 6-(4- methylphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 277.2 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.71 (br. s., 1 H), 7.29 (d, J = 7.79 Hz, 2 H), 7.23 (d, J = 8.24 Hz, 2H), 5.83 (s, 1 H), 4.39 (t, J = 5.04 Hz, 2 H), 3.63 (t, J = 5.72 Hz, 2H), 3.19 (s, 3 H), 2.43 (s, 3 H) 286

6-(4- hydroxyphenyl)- 1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 279.1 1 H NMR (400 MHz, DMSO-d6) d ppm 12.73(br. s., 1 H), 9.97 (s, 1 H), 7.29 (d, J = 8.24 Hz, 2 H), 6.85 (d, J =8.24 Hz, 2 H), 5.72 (s, 1 H), 4.29 (t, J = 5.95 Hz, 2 H), 3.46 (t, J =6.41 Hz, 2 H), 3.02 (s, 3 H) 287

6-(3- hydroxyphenyl)- 1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 279.1 1 H NMR (301 MHz, DMSO-d6) δ ppm 12.75(br. s., 1 H), 9.85 (s, 1 H), 7.27 (dd, J = 7.80, 7.80 Hz, 1 H),6.82-6.90 (m, 2 H), 6.79 (br. s., 1 H), 5.72 (s, 1 H), 4.20 (t, J = 6.54Hz, 1 H), 3.45 (t, J = 6.08 Hz, 2 H), 3.00 (s, 3 H) 288

6-(2- hydroxyphenyl)- 1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 279.1 1 H NMR (400 MHz, METHANOL-d3) δ ppm7.34 (td, J = 7.90, 1.60 Hz, 1 H), 7.23 (dd, J = 7.67, 1.49 Hz, 1 H),6.94 (t, J = 7.44 Hz, 1 H), 6.90 (d, J = 8.24 Hz, 1 H), 5.73 (s, 1 H),4.76 (ddd, J = 13.51, 5.72, 4.58 Hz, 1 H), 3.97 (dt, J = 13.91, 7.13 Hz,1 H), 3.65 (ddd, J = 10.25, 7.38, 6.64 Hz, 1 H), 3.45 (ddd, J = 10.42,6.41, 4.24 Hz, 1 H), 3.06 (s, 3 H) 289

6-(3- fluorophenyl)-1- (2-methoxyethyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 281.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.00 (br. s., 1H), 7.47 (ddd, J = 8.10, 8.10, 5.70 Hz, 1 H), 7.22 (ddd, J = 8.10, 8.10,2.10 Hz, 1 H), 7.07-7.16 (m, 2 H), 5.85 (d, J = 1.37 Hz, 1 H), 4.36 (br.s., 2 H), 3.66 (br. s., 2 H), 3.21 (s, 3 H) 290

6-(4- fluorophenyl)-1- (2-methoxyethyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 281.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.57 (br. s, 1 H),7.35 (dd, J = 8.93, 5.27 Hz, 2 H), 7.18 (dd, J = 8.20 Hz, 2 H), 5.82 (s,1 H), 4.35 (t, J = 5.04 Hz, 2 H), 3.65 (t, J = 5.50 Hz, 2 H), 3.20 (s, 3H) 291

3-[3-(2- methoxyethyl)- 6-oxo-2-thioxo- 1,2,3,6- tetrahydropyrimidin-4-yl]benzonitrile 288.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.70 (br.s., 1 H), 7.81 (d, J = 7.33 Hz, 1 H), 7.71 (s, 1 H), 7.55-7.66 (m, 2 H),5.82 (d, J = 1.83 Hz, 1 H), 4.29 (br. s., 2 H), 3.67 (br. s., 2 H), 3.23(s, 3 H) 292

6-[2- (hydroxymethyl) phenyl]-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 293.0 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.77(br. s., 1 H), 7.43- 7.56 (m, 2 H), 7.30-7.41 (m, 2 H), 5.76 (s, 1 H),5.27 (t, J = 5.38 Hz, 1 H), 4.38 (d, J = 5.27 Hz, 2 H), 4.26-4.35 (m, 1H), 3.69- 3.82 (m, 1 H), 3.45-3.55 (m, 1 H), 3.39 (dt, J = 9.85, 6.75Hz, 1 H), 2.97 (s, 3 H) 293

1-(2- methoxyethyl)- 6-(3- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 293.2 1 H NMR (400 MHz, METHANOL-d3) δ ppm7.42 (t, J = 8.24, 8.24 Hz, 1 H), 7.08 (ddd, J = 8.24, 2.75, 0.92 Hz, 1H), 7.03 (dd, J = 2.75, 1.37 Hz, 1 H), 6.99 (ddd, J = 7.79, 1.83, 0.92Hz, 2 H), 5.79 (s, 1 H), 4.39 (t, J = 5.50 Hz, 2 H), 3.84 (s, 3 H), 3.64(t, J = 5.72 Hz, 2 H), 3.15 (s, 3 H) 294

1-(2- methoxyethyl)- 6-(4- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 293.2 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.62 (br. s., 1 H), 7.28 (d, J = 8.70 Hz, 2 H), 6.99 (d, J = 8.70 Hz, 2H), 5.83 (d, J = 1.37 Hz, 1 H), 4.41 (t, J = 5.50 Hz, 2 H), 3.87 (s, 3H), 3.64 (t, J = 5.72 Hz, 2 H), 3.20 (s, 3 H) 295

1-(2- methoxyethyl)- 6-(6- methoxypyridin- 3-yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 294.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.53 (br. s., 1 H), 8.16 (d, J = 1.83 Hz, 1 H), 7.58 (dd, J = 8.70, 2.29Hz, 1 H), 6.85 (dd, J = 8.70, 0.92 Hz, 1 H), 5.84 (d, J = 2.29 Hz, 1 H),4.37 (br. s., 2 H), 4.01 (s, 3 H), 3.68 (t, J = 5.27 Hz, 3 H), 3.23 (s,3 H) 296

1-(2- methoxyethyl)- 6-(3- methoxypyridin- 4-yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 294.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.61 (br. s., 1 H), 8.42 (s, 1 H), 8.40 (d, J = 4.81 Hz, 1 H), 7.18 (d,J = 4.81 Hz, 1 H), 5.77 (d, J = 2.29 Hz, 1 H), 4.73 (dt, J = 13.97, 3.43Hz, 1 H), 3.97 (s, 3 H), 3.80 (td, J = 9.62, 3.89 Hz, 1 H), 3.68 (ddd, J= 13.80, 9.33, 4.58 Hz, 1 H), 3.36 (dt, J = 10.08, 3.89 Hz, 1 H), 3.14(s, 3 H) 297

1-(2- methoxyethyl)- 6-(2- methoxypyridin- 4-yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 294.2 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.59 (br. s., 1 H), 8.29 (dd, J = 5.04, 0.92 Hz, 1 H), 6.85 (dd, J =5.27, 1.60 Hz, 1 H), 6.74 (d, J = 1.37 Hz, 1 H), 5.81 (d, J = 2.29 Hz, 1H), 4.35 (br. s., 2 H), 4.00 (s, 3 H), 3.66 (t, J = 5.27 Hz, 2 H), 3.22(s, 3 H) 298

6-(4- chlorophenyl)-1- (2-methoxyethyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 297.1 1 H NMR (400 MHz, METHANOL-d3) δ ppm 7.53 (d, J = 7.79Hz, 2 H), 7.45 (d, J = 8.24 Hz, 2 H), 5.79 (s, 1 H), 4.38 (t, J = 5.04Hz, 2 H), 3.62 (t, J = 5.72 Hz, 2 H), 3.16 (s, 3 H) 299

6-(2- chlorophenyl)-1- (2-methoxyethyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 297.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.57 (br. s., 1H), 7.44-7.52 (m, 2 H), 7.39-7.44 (m, 1 H), 7.34- 7.39 (m, 1 H), 5.83(d, J = 1.37 Hz, 1 H), 4.66-4.76 (m, 1 H), 3.73-3.86 (m, 2 H), 3.41-3.47(m, 1 H), 3.17 (s, 3 H) 300

6-(3- chlorophenyl)-1- (2-methoxyethyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 297.1 1 H NMR (400 MHz, METHANOL-d3) δ ppm 7.47- 7.57 (m, 3H),7.39 (ddd, J = 7.30, 1.40 Hz, 1 H), 5.80 (s, 1 H), 4.36 (br. s., 2 H),3.64 (t, J = 5.50 Hz, 2 H), 3.16 (s, 3 H) 301

6-(1H-indol-6- yl)-1-(2- methoxyethyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 302.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.55 (br. s., 1H), 8.44 (br. s., 1 H), 7.73 (d, J = 8.24 Hz, 1 H), 7.41 (s, 1 H), 7.38(dd, J = 3.43, 2.52 Hz, 1 H), 7.05 (dd, J = 8.24, 1.37 Hz, 1 H), 6.65(ddd, J = 3.09, 1.95, 0.92 Hz, 1 H), 5.91 (s, 1 H), 4.46 (br. s., 2 H),3.63 (br. s., 2 H), 3.15 (s, 3 H) 302

6-(1H-indol-2- yl)-1-(2- methoxyethyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 302.1 1 H NMR (400 MHz, DMSO-d6) d ppm 12.81 (s, 1 H), 11.66(br. s., 1 H), 7.59 (d, J = 7.79 Hz, 1 H), 7.41 (d, J = 8.24 Hz, 1 H),7.18 (t, J = 7.67 Hz, 1 H), 7.05 (t, J = 7.44 Hz, 1 H), 6.84 (s, 1 H),6.03 (s, 1 H), 4.55 (t, J = 5.84 Hz, 2 H), 3.52 (t, J = 5.84 Hz, 2 H),3.01 (s, 3 H) 303

6-(1H-indol-5- yl)-1-(2- methoxyethyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 302.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.54 (br. s., 1H), 8.39 (br. s., 1 H), 7.61 (s, 1 H), 7.48 (d, J = 8.24 Hz, 1 H), 7.34(t, J = 2.75 Hz, 1 H), 7.12 (dd, J = 8.36, 1.49 Hz, 1 H), 6.63 (d, J =2.06 Hz, 1 H), 5.90 (d, J = 2.52 Hz, 1 H), 4.45 (br. s., 2 H), 3.60 (t,J = 5.84 Hz, 2 H), 3.08-3.18 (m, 3 H) 304

6-(1H-indol-4- yl)-1-(2- methoxyethyl)- 2-thioxo-2,3- dihydropyrimidin--4(1H)-one 302.1 1 H NMR (400 MHz, METHANOL-d3) δ ppm 7.55 (d, J = 8.01Hz, 1 H), 7.39 (d, J = 3.21 Hz, 1 H), 7.23 (t, J = 7.79 Hz, 1 H), 7.09(d, J = 7.10 Hz, 1 H, 6.31 (d, J = 2.98 Hz, 1 H), 5.86 (s, 1 H),4.57-4.70 (m, 1 H), 4.15 (dt, J = 13.34, 6.50 Hz, 1 H), 3.56 (dt, J =10.19, 6.58 Hz, 1 H), 3.42 (ddd, J = 10.76, 6.18, 5.04 Hz, 1 H), 2.93(s, 3 H) 305

6-(1- benzofuran-3- yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 303.0 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.69 (br. s., 1 H), 7.94 (s, 1 H), 7.59 (d, J = 8.24 Hz, 1 H), 7.47 (d,J = 7.79 Hz, 1 H), 7.42 (td, J = 7.67, 1.14 Hz, 1 H), 7.36 (t, J = 6.87Hz, 1 H), 6.02 (d, J = 2.52 Hz, 1 H), 4.49 (br. s., 2 H), 3.63-3.72 (m,2 H), 3.19 (s, 3 H) 306

6-(1- benzofuran-2- yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 303.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.54 (br. s., 1 H), 7.68 (d, J = 7.56 Hz, 1 H), 7.55 (d, J = 8.24 Hz, 1H), 7.44 (t, J = 7.67 Hz, 1 H), 7.34 (t, J = 7.44 Hz, 1 H), 7.23 (s, 1H), 6.25 (d, J = 2.29 Hz, 1 H), 4.66 (br. s., 2 H), 3.78 (t, J = 5.84Hz, 2 H), 3.25 (s, 3 H) 307

6-(1- benzofuran-7- yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 303.4 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm10.48 (br. s., 1 H), 7.75 (dd, J = 7.79, 1.37 Hz, 1 H), 7.67 (d, J =2.29 Hz, 1 H), 7.35 (dd, J = 7.30, 7.30 Hz, 1 H), 7.27 (dd, J = 7.56,1.15 Hz, 1 H), 6.87 (d, J = 2.29 Hz, 1 H), 5.98 (s, 1 H), 4.57-4.76 (m,1 H), 3.93-4.10 (m, 1 H), 3.59-3.75 (m, 1 H), 3.33-3.50 (m, 1 H), 3.03(s, 3 H) 308

6-(2,3-dihydro- 1-benzofuran-5- yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 305.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.97 (br. s., 1 H), 7.15 (d, J = 1.37 Hz, 1 H), 7.08 (dd, J = 8.01, 2.06Hz, 1 H), 6.85 (d, J = 8.24 Hz, 1 H), 5.84 (d, J = 2.75 Hz, 1 H), 4.67(t, J = 8.70 Hz, 2 H), 4.43 (t, J = 5.50 Hz, 1 H), 3.64 (t, J = 5.50 Hz,2 H), 3.28 (t, J = 8.93 Hz, 2 H), 3.20 (s, 3 H) 309

6-(1,3- benzodioxol-5- yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 307.1 1 H NMR (400 MHz, METHANOL-d3) δ ppm6.96 (d, J = 1.83 Hz, 1 H), 6.94 (s, 1 H), 6.92 (d, J = 1.83 Hz, 1 H),6.05 (s, 2 H), 5.78 (s, 1 H), 4.43 (t, J = 5.72 Hz, 2 H), 3.63 (t, J =5.72 Hz, 2 H), 3.17 (s, 3 H) 310

6-(2- ethoxyphenyl)- 1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 307.1 1 H NMR (400 MHz, METHANOL-d3) δ ppm7.51 (ddd, J = 8.36, 7.44, 1.60 Hz, 1 H), 7.32 (dd, J = 7.56, 1.60 Hz, 1H), 7.11 (d, J = 8.70 Hz, 1 H), 7.08 (t, J = 7.30 Hz, 1 H), 5.75 (s, 1H), 4.70-4.79 (m, 1 H), 4.15 (q, J = 7.20 Hz, 2 H), 3.82- 3.92 (m, 1 H),3.69 (ddd, J = 10.08, 7.79, 5.95 Hz, 1 H), 3.43 (ddd, J = 10.19, 6.30,4.12 Hz, 1 H), 3.08 (s, 3 H), 1.36 (t, J = 7.10 Hz, 3 H) 311

6-(4- ethoxyphenyl)- 1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 307.2 1 H NMR (400 MHz, METHANOL-d3) δ ppm7.36 (d, J = 8.70 Hz, 2 H), 7.03 (d, J = 8.70 Hz, 2 H), 5.76 (s, 1 H),4.44 (t, J = 5.50 Hz, 2 H), 4.10 (q, J = 6.87 Hz, 2 H), 3.61 (t, J =5.95 Hz, 2 H), 3.14 (s, 3 H), 1.42 (t, J = 7.10 Hz, 3 H) 312

1-(2- methoxyethyl)- 6-(2-methoxy-5- methylphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 307.2 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.46 (br. s, 1 H), 7.27-7.31 (m, 1 H), 7.03 (d, J = 1.83 Hz, 1 H), 6.86(d, J = 8.20 Hz, 1 H), 5.81 (d, J = 2.29 Hz, 1 H), 4.62-4.72 (m, 1 H),3.84-3.93 (m, 1 H), 3.82 (s, 3 H), 3.72 (ddd, J = 10.19, 7.90, 5.72 Hz,1 H), 3.44 (ddd, J = 10.19, 6.30, 4.12 Hz, 1 H), 3.14 (s, 3 H), 2.34 (s,3 H) 313

6-(6- ethoxypyridin-3- yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 308.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.60 (br. s., 1 H), 8.13 (d, J = 2.29 Hz, 1 H), 7.57 (dd, J = 8.47, 2.06Hz, 1 H), 6.82 (d, J = 8.70 Hz, 1 H), 5.84 (s, 1 H), 4.42 (q, J = 7.02Hz, 2 H), 4.37 (br. s, 2 H), 3.68 (t, J = 5.04 Hz, 2 H), 3.23 (s, 3 H),1.43 (t, J = 6.87 Hz, 3 H) 314

2′-(dimethylamino)- 3-(2- methoxyethyl)- 2-thioxo-2,3- dihydro-4,5′-bipyrimidin- 6(1H)-one 308.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.83(br. s., 1 H), 8.30 (s, 2 H), 5.83 (d, J = 2.75 Hz, 1 H), 4.43 (br. s.,2 H), 3.72 (t, J = 5.04 Hz, 2 H), 3.26 (s, 3 H), 3.26 (s, 6 H) 315

6-(3-fluoro-4- methoxyphenyl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 311.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.58 (br. s., 1 H), 7.13 (dd, J = 11.22, 2.06 Hz, 1 H), 7.07 (dd, J =8.70, 1.83 Hz, 1 H), 7.03 (dd, J = 7.80, 7.80 Hz, 1 H), 5.81 (d, J =2.29 Hz, 1 H), 4.37 (br. s., 2 H), 3.95 (s, 3 H), 3.65 (t, J = 5.27 Hz,1 H), 3.21 (s, 3 H) 316

6-(2-fluoro-4- methoxyphenyl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 311.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.49 (br. s., 1 H), 7.22 (t, J = 8.47 Hz, 1 H), 6.81 (dd, J = 8.24, 2.29Hz, 1 H), 6.72 (dd, J = 11.68, 2.06 Hz, 1 H), 5.86 (d, J = 2.75 Hz, 1H), 4.60-4.70 (m, 1 H), 4.02- 4.12 (m, 1 H), 3.87 (s, 3 H), 3.71-3.81(m, 1 H), 3.48 (dd, J = 9.85, 4.81 Hz, 1 H), 3.18 (s, 3 H) 317

6-(5-fluoro-2- methoxyphenyl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 311.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.58 (br. s, 1 H), 7.17 (ddd, J = 9.05, 7.90, 3.21 Hz, 1 H), 6.98 (dd, J= 7.79, 3.21 Hz, 1 H), 6.89 (dd, J = 9.16, 4.12 Hz, 1 H), 5.79 (d, J =2.29 Hz, 1 H), 4.65-4.75 (m, 1 H), 3.82 (s, 3 H), 3.72-3.80 (m, 2 H),3.37-3.43 (m, 1 H), 3.16 (s, 3 H) 318

6-(4-fluoro-2- methoxyphenyl)- 1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 311.2 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.58 (br. s., 1 H), 7.21 (dd, J = 8.24, 6.41 Hz, 1H ), 6.78 (ddd, J =8.20, 8.20, 2.30 Hz, 1 H), 6.71 (dd, J = 10.53, 2.29 Hz, 1 H), 5.79 (s,1 H), 4.65-4.75 (m, 1 H), 3.85 (s, 3 H), 3.69- 3.83 (m, 2 H), 3.38-3.47(m, 1 H), 3.16 (s, 2 H) 319

1-(2- methoxyethyl)- 6-(1-naphthyl)- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 313.1 1 H NMR (400 MHz, METHANOL-d3) δ ppm 8.07 (dd, J = 6.87,2.75 Hz, 1 H), 7.98- 8.04 (m, 1 H), 7.66-7.71 (m, 1 H), 7.58-7.66 (m, 4H), 5.92 (s, 1 H), 4.50-4.60 (m, 1 H), 3.70-3.80 (m, 1 H), 3.59-3.67 (m,1 H), 3.43 (ddd, J = 10.42, 6.07, 4.58 Hz, 1 H), 2.98 (s, 3 H) 320

1-(2- methoxyethyl)- 6-quinolin-3-yl- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 314.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.99 (br. s., 1H), 8.89 (d, J = 2.29 Hz, 1 H), 8.17-8.23 (m, 2 H), 7.91 (dd, J = 8.01,1.14 Hz, 1 H), 7.87 (ddd, J = 8.59, 6.98, 1.37 Hz, 1 H), 7.69 (ddd, J =8.24, 6.87, 1.37 Hz, 1 H), 5.95 (d, J = 0.92 Hz, 1 H), 4.36-4.46 (m, 2H), 3.68 (t, J = 4.81 Hz, 2 H), 3.21 (s, 3 H) 321

1-(2- methoxyethyl)- 6-quinolin-5-yl- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 314.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.50 (br. s., 1H), 9.02 (dd, J = 4.12, 1.60 Hz, 1 H), 8.28 (d, J = 8.47 Hz, 1 H), 8.02(d, J = 8.47 Hz, 1 H), 7.81 (dd, J = 8.47, 7.33 Hz, 1 H), 7.56 (dd, J =7.10, 0.69 Hz, 1 H), 7.51 (dd, J = 8.59, 4.24 Hz, 1 H), 5.96 (d, J =1.37 Hz, 1 H), 4.45 (dt, J = 14.14, 4.84 Hz, 1 H), 3.83- 3.98 (m, 1 H),3.60 (ddd, J = 10.48, 6.35, 4.69 Hz, 1 H), 3.49 (dt, J = 10.30, 4.92 Hz,1 H), 3.02 (s, 3 H) 322

1-(2- methoxyethyl)- 6-quinolin-8-yl- 2-thioxo-2,3- dihydropyrimidin-4(1H)-one 314.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.82 (br. s., 1H), 8.95 (dd, J = 4.12, 1.83 Hz, 1 H), 8.25 (dd, J = 8.47, 1.60 Hz, 1H), 8.01 (dd, J = 8.24, 1.37 Hz, 1 H), 7.74 (dd, J = 6.87, 1.37 Hz, 1H), 7.66 (dd, J = 8.24, 6.87 Hz, 1 H), 7.52 (dd, J = 8.24, 4.12 Hz, 1H), 5.93 (d, J = 2.29 Hz, 1 H), 4.65 (ddd, J = 13.74, 5.04, 3.66 Hz, 1H), 3.75 (ddd, J = 10.30, 8.24, 5.50 Hz, 1 H), 3.65 (ddd, J = 13.97,8.24, 5.72 Hz, 1 H), 3.36 (ddd, J = 10.30, 5.50, 3.66 Hz, 1 H), 3.07 (s,3 H) 323

6-(1-benzothien- 2-yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 319.4 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.81 (br. s., 1 H), 7.80-7.92 (m, 2 H), 7.51 (s, 1 H), 7.42-7.48 (m, 2H), 6.10 (d, J = 2.29 Hz, 1 H), 4.57 (t, J = 5.50 Hz, 2 H), 3.74 (t, J =5.50 Hz, 2 H), 3.26 (s, 3 H) 324

6-(1-benzothien- 3-yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 319.4 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.88 (br. s., 1 H), 7.87-7.98 (m, 1 H), 7.67 (s, 1 H), 7.52-7.60 (m, 1H), 7.41-7.51 (m, 2 H), 5.98 (d, J = 2.29 Hz, 1 H), 4.66 (dt, J = 13.97,4.10 Hz, 1 H), 3.92-4.07 (m, 1 H), 3.69-3.82 (m, 1 H), 3.41-3.50 (m, 1H), 3.11 (s, 3 H) 325

3-[3-(2- methoxyethyl)- 6-oxo-2-thioxo- 1,2,3,6- tetrahydropyrimidin-4-yl]-N- methylbenzamide 320.1 1 H NMR (400 MHz, METHANOL-d3) δ ppm7.89- 7.99 (m, 1 H), 7.86 (s, 1 H), 7.54-7.65 (m, 2 H), 5.81 (s, 1H),4.36 (br. s., 2 H), 3.60 (t, J = 5.50 Hz, 2 H), 3.11 (s, 3 H), 2.92 (s,3 H) 326

6-(2,3-dihydro- 1,4-benzodioxin-6- yl)-1-(2- methoxyethyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 321.1 1 H NMR (400 MHz,CHLOROFORM-d) δ ppm 9.49 (br. s., 1 H), 6.94 (d, J = 8.24 Hz, 1 H), 6.87(d, J = 2.29 Hz, 1 H), 6.80 (dd, J = 8.24, 2.29 Hz, 1 H), 5.82 (d, J =2.29 Hz, 1 H), 4.42 (t, J = 5.27 Hz, 2 H), 4.27-4.35 (m, 4 H), 3.65 (t,J = 5.72 Hz, 2 H), 3.22 (s, 3 H) 327

6-(4- isopropoxyphenyl)- 1-(2-methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 321.2 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.59 (br. s., 1 H), 7.25 (d, J = 9.16 Hz, 2 H), 6.95 (d, J = 8.70 Hz, 2H), 5.83 (d, J = 2.29 Hz, 1 H), 4.62 (spt, J = 6.00 Hz, 1 H), 4.42 (t, J= 5.50 Hz, 2 H), 3.64 (t, J = 5.72 Hz, 2 H), 3.18-3.21 (m, 3 H), 1.38(d, J = 6.41 Hz, 6 H) 328

6-(2- isopropoxyphenyl)- 1-(2-methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 321.2 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm10.13 (br. s., 1 H), 7.45 (ddd, J = 8.00, 7.80, 1.60 Hz, 1 H), 7.23 (dd,J = 7.56, 1.60 Hz, 1 H), 7.02 (ddd, J = 7.80, 7.70, 0.92 Hz, 1 H), 6.95(d, J = 8.24 Hz, 1 H), 5.82 (s, 1 H), 4.74 (ddd, J = 13.74, 5.04, 3.66Hz, 1 H), 4.62 (spt, J = 6.00 Hz, 1 H), 3.86 (ddd, J = 13.85, 7.90, 6.18Hz, 1 H), 3.71 (ddd, J = 10.08, 8.24, 5.50 Hz, 1 H), 3.45 (ddd, J =10.08, 6.18, 3.89 Hz, 1 H), 3.13 (s, 3 H), 1.35 (d, J = 5.95 Hz, 3 H),1.28 (d, J = 5.95 Hz, 3 H) 329

6-(2,3- dimethoxyphenyl)- 1-(2-methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 323.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.48 (br. s., 1 H), 7.15 (dd, J = 8.20 Hz, 1 H), 7.06 (dd, J = 8.24,1.37 Hz, 1 H), 6.83 (dd, J = 7.79, 1.37 Hz, 1 H), 5.85 (d, J = 2.75 Hz,1 H), 4.67 (dt, J = 13.74, 4.58 Hz, 1 H), 3.92 (s, 3 H), 3.86-4.00 (m, 1H), 3.82 (s, 3 H), 3.72 (ddd, J = 10.30, 8.01, 5.95 Hz, 1 H), 3.44 (ddd,J = 10.30, 6.18, 4.12 Hz, 1 H), 3.14 (s, 3 H) 330

6-(3,5- dimethoxyphenyl)- 1-(2-methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 323.1 1 H NMR (300 MHz, CHLOROFORM-d) δ ppm10.17 (br. s., 1 H), 6.55 (t, J = 2.30 Hz, 1 H), 6.48 (d, J = 2.30 Hz, 2H), 5.88 (d, J = 1.84 Hz, 1 H), 4.39 (t, J = 5.51 Hz, 2 H), 3.82 (s, 6H), 3.68 (t, J = 5.51 Hz, 2 H), 3.22 (s, 3 H) 331

6-(3,4- dimethoxyphenyl)- 1-(2-methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 323.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm10.27 (br. s., 1 H), 6.85-6.98 (m, 3 H), 5.88 (s, 1 H), 4.33- 4.49 (m, 2H), 3.94 (s, 3 H), 3.91 (s, 3 H), 3.63-3.75 (m, 2 H), 3.22 (s, 3 H) 332

6-(2,6- dimethoxypyridin- 3-yl)-1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 324.1 1 H NMR (400 MHz, CHLOROFORM-d) d ppm9.77 (br. s., 1 H), 7.43 (d, J = 7.79 Hz, 1 H), 6.42 (d, J = 8.24 Hz, 1H), 5.79 (s, 1 H), 4.75 (ddd, J = 13.60, 3.50, 3.50 Hz, 1 H), 3.98 (s, 3H), 3.97 (s, 3 H), 3.85 (ddd, J = 13.74, 8.70, 5.50 Hz, 1 H), 3.77 (ddd,J = 9.20, 9.20, 4.10 Hz, 1 H), 3.43 (ddd, J = 9.60, 4.60, 4.60 Hz, 1 H),3.18 (s, 3 H) 333

6-(5-chloro-2- methoxyphenyl)- 1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 327.1 1 H NMR (400 MHz, METHANOL-d3) δ ppm7.51 (dd, J = 8.70, 2.75 Hz, 1 H), 7.35 (d, J = 2.75 Hz, 1 H), 7.13 (d,J = 9.16 Hz, 1 H), 5.77 (s, 1 H), 4.67-4.76 (m, 1 H), 3.89 (s, 3 H),3.73-3.81 (m, 2 H), 3.38- 3.45 (m, 1 H), 3.12 (s, 3 H) 334

6-(2-chloro-4- methoxyphenyl)- 1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 327.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm10.18 (br. s., 1 H), 7.26 (d, J = 8.70 Hz, 1 H), 7.00 (d, J = 2.29 Hz, 1H), 6.92 (dd, J = 8.93, 2.06 Hz, 1 H), 5.84 (s, 1 H), 4.64-4.78 (m, 1H), 3.87 (s, 3 H), 3.76-3.85 (m, 2 H), 3.39-3.52 (m, 1 H), 3.19 (s, 3 H)335

6-(4-chloro-2- methoxyphenyl)- 1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 327.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.96 (br. s., 1 H), 7.17 (d, J = 7.79 Hz, 1 H), 7.06 (dd, J = 8.24, 1.83Hz, 1 H), 6.97 (d, J = 1.37 Hz, 1 H), 5.79 (s, 1 H), 4.64-4.77 (m, 1 H),3.86 (s, 1 H), 3.72-3.82 (m, 2 H), 3.36-3.47 (m, 1 H), 3.16 (s, 3 H) 336

4-[3-(2- methoxyethyl)- 6-oxo-2-thioxo- 1,2,3,6- tetrahydropyrimidin-4-yl]-N,N- dimethylbenzamide 334.2 1 H NMR (400 MHz, METHANOL-d3) δ ppm7.53- 7.60 (m, 4 H), 5.82 (s, 1 H), 4.40 (t, J = 5.27 Hz, 2 H), 3.62 (t,J = 5.50 Hz, 2 H), 3.14 (s, 3 H), 3.13 (s, 3 H), 3.03 (s, 3 H) 337

6-(5-isopropyl-2- methoxyphenyl)- 1-(2- methoxyethyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 335.2 1 H NMR (400 MHz, METHANOL-d3) δ ppm7.37 (dd, J = 8.59, 2.18 Hz, 1 H), 7.16 (d, J = 2.29 Hz, 1 H), 7.03 (d,J = 8.70 Hz, 1 H), 5.72 (s, 1 H), 4.69 (dt, J = 13.80, 4.89 Hz, 1 H),3.83 (s, 3 H), 3.76-3.82 (m, 1 H), 3.66 (ddd, J = 10.19, 7.79, 6.07 Hz,1 H), 3.41 (ddd, J = 10.25, 6.24, 4.12 Hz, 1 H), 3.06 (s, 3 H), 2.90(spt, J = 7.10 Hz, 1 H), 1.24 (dd, J = 6.87, 2.98 Hz, 6 H) 338

6-[6- (dimethylamino)-4- methoxypyridin- 3-yl]-1-(2- methoxyethyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 337.2 1 H NMR (400 MHz,CHLOROFORM-d) δ ppm 9.61 (br. s., 1 H), 7.90 (s, 1 H), 7.27 (s, 1 H),5.91 (s, 1 H), 4.78 (dt, J = 14.08, 3.72 Hz, 1 H), 3.87 (s, 3 H), 3.82(dt, J = 13.74, 6.41 Hz, 1 H), 3.67-3.76 (m, 1 H), 3.42-3.51 (m, 1 H),3.21 (s, 3 H), 3.16 (s, 6 H) 339

1-(2- methoxyethyl)- 6-(2-methoxy-1- naphthyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 343.4 1 H NMR (400 MHz, CHLOROFORM-d) 9.58(s, 1 H), 8.02 (d, 1 H), 7.82 (d, 1 H), 7.50-7.58 (m, 2 H), 7.39-7.43(dd, 1 H), 7.31 (d, 1 H), 5.89 (s, 1 H), 4.26-4.33 (m, 1 H), 4.02- 4.11(m, 1 H), 3.97 (s, 3 H), 3.51-3.57 (m, 1 H), 3.31-3.39 (m, 1 H), 2.88(s, 3 H) 340

1-(2- methoxyethyl)- 2-thioxo-6-[3- (trifluoromethoxy) phenyl]-2,3-dihydropyrimidin- 4(1H)-one 347.1 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.56 (br. s., 0 H), 7.53 (dd, J = 7.80, 7.80 Hz, 1 H), 7.37 (d, J = 9.16Hz, 1 H), 7.25-7.31 (m, 2 H), 5.84 (d, J = 2.29 Hz, 1 H), 4.34 (br. s, 2H), 3.66 (br. s, 2 H), 3.20 (s, 3 H) 341

1-(2- methoxyethyl)- 6-(3-methoxy- 5,6,7,8- tetrahydro-naphthalen-2-yl)-2- thioxo-2,3- dihydropyrimidin- 4(1H)-one 347.5 1 HNMR (400 MHz, METHANOL-d3) δ ppm 6.96 (s, 1 H), 6.78 (s, 1 H), 5.70 (s,1 H), 4.60-4.72 (m, 1 H), 3.86 (dt, J = 14.03, 7.30 Hz, 1 H), 3.81 (s, 3H), 3.67 (ddd, J = 10.30, 7.56, 6.41 Hz, 1 H), 3.41 (ddd, J = 10.36,6.35, 4.12 Hz, 1 H), 3.07 (s, 3 H), 2.82 (br. s., 2 H), 2.72 (br. s., 2H), 1.75- 1.86 (m, 4 H) 342

1-(2- methoxyethyl)- 2-thioxo-6- (3,4,5- trimethoxyphenyl)-2,3-dihydropyrimidin- 4(1H)-one 353.1 1 H NMR (400 MHz, CHLOROFORM-d) δppm 9.91 (br. s., 1 H), 6.59 (s, 2 H), 5.88 (d, J = 2.29 Hz, 1 H), 4.39(t, J = 5.50 Hz, 2 H), 3.92 (s, 3 H), 3.88 (s, 6 H), 3.73 (t, J = 5.27Hz, 2 H), 3.24 (s, 3 H) 343

1-(2- methoxyethyl)- 2-thioxo-6- (2,3,4- trimethoxyphenyl)-2,3-dihydropyrimidin- 4(1H)-one 353.1 1 H NMR (400 MHz, CHLOROFORM-d) δppm 9.49 (br. s., 1 H), 6.92 (d, J = 8.70 Hz, 1 H), 6.73 (d, J = 8.70Hz, 1 H), 5.83 (d, J = 2.29 Hz, 1 H), 4.62- 4.71 (m, 1 H), 3.93-3.98 (m,1 H), 3.92 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.73 (ddd, J = 10.08,8.01, 5.72 Hz, 1 H), 3.46 (ddd, J = 10.08, 6.18, 3.89 Hz, 1 H), 3.17 (s,3 H) 344

6-(4-fluoro-5- isopropyl-2- methoxyphenyl)-1-(2- methoxyethyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 353.1 1 H NMR (400 MHz,METHANOL-d3) δ ppm 7.23 (d, J = 8.24 Hz, 1 H), 6.87 (d, J = 12.14 Hz, 1H), 5.72 (s, 1 H), 4.69 (dt, J = 13.45, 4.15 Hz, 1 H), 3.84 (s, 3 H),3.64-3.81 (m, 2 H), 3.40 (ddd, J = 9.79, 5.55, 3.66 Hz, 1 H), 3.19 (spt,J = 7.10 Hz, 1 H), 3.10 (s, 3 H), 1.24 (d, J = 6.87 Hz, 6 H) 345

1-(2- methoxyethyl)- 6-(8-methoxy-2- methylquinolin- 5-yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 358.2 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm9.86 (br. s., 1 H), 7.84 (d, J = 8.70 Hz, 1 H), 7.42 (d, J = 8.70 Hz, 2H), 7.10 (d, J = 8.24 Hz, 1 H), 5.95 (d, J = 2.29 Hz, 1 H), 4.49 (dt, J= 14.08, 5.09 Hz, 1 H), 4.15 (s, 3H), 3.85-4.00 (m, 1 H), 3.61 (ddd, J =10.99, 6.87, 4.58 Hz, 1 H), 3.49 (dt, J = 10.30, 5.38 Hz, 1 H), 3.04 (s,3 H), 2.84 (s, 3 H) 346

6-[5-fluoro-2- (trifluoromethoxy) phenyl]-1-(2- methoxyethyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 365.1 1 H NMR (400 MHz,CHLOROFORM-d) δ ppm 9.58 (br. s., 1 H), 7.31-7.39 (m, 1 H), 7.26-7.29(m, 1 H), 7.15 (dd, J = 7.90, 3.09 Hz, 1 H), 5.83 (d, J = 2.52 Hz, 1 H),4.68 (dt, J = 14.20, 3.32 Hz, 1 H), 3.88 (td, J = 9.85, 3.66 Hz, 1 H),3.72 (ddd, J = 13.91, 9.45, 3.89 Hz, 1 H), 3.39 (dt, J = 10.36, 3.75 Hz,1 H), 3.19 (s, 3 H) 347

4-[3-(2- methoxyethyl)- 6-oxo-2-thioxo- 1,2,3,6- tetrahydropyrimidin-4-yl]-N,N- dimethylbenzene- sulfonamide 370.1 1 H NMR (400 MHz,CHLOROFORM-d) δ ppm 9.84 (br. s., 1 H), 7.90 (d, J = 6.87 Hz, 2 H), 7.56(d, J = 6.87 Hz, 2 H), 5.84 (s, 1 H), 4.32 (br. s., 2 H), 3.66 (t, J =4.35 Hz, 2 H), 3.20 (s, 3 H), 2.81 (s, 6 H) 348

3-[3-(2- methoxyethyl)- 6-oxo-2-thioxo- 1,2,3,6- tetrahydropyrimidin-4-yl]-N,N- dimethylbenzene- sulfonamide 370.1 1 H NMR (400 MHz,CHLOROFORM-d) δ ppm 10.14 (br. s., 1 H), 7.91 (ddd, J = 8.24, 1.80, 1.50Hz, 1 H), 7.84 (dd, J = 1.60, 1.60 Hz, 1 H), 7.69 (dd, J = 7.80, 7.80Hz, 1 H), 7.59 (ddd, J = 7.80, 1.40, 1.40 Hz, 1 H), 5.85 (d, J = 1.83Hz, 1 H), 4.31 (br. s, 2 H), 3.67 (br. s., 2 H), 3.21 (s, 3 H), 2.77 (s,6 H)

Additions to I. Beta Keto Ester Route Section E. Ester Route SectionPreparation 19

tert-Butyl 3-(2-(2-hydroxyethoxy)phenyl)-3-oxopropanoate

To a solution of tert-butyl acetate (7.96 g, 68.5 mmol) in anhydrous THF(100 mL) was added freshly prepared lithium diisopropyl amine (37 mL,1.85 M in THF) dropwise over 15 min at −78° C., and the mixture wasstirred at −78° C. for 30 min. 2H-benzo[e][1,4]dioxepin-5(3H)-one (10.2g, 62.3 mmol) was added dropwise as a solution in THF (50 mL) at −78 C,and stirring was continued for 30 min. Saturated NaHCO3 solution wasadded and the mixture was extracted with EtOAc. The organic layer wasdried (Na₂SO₄), and concentrated under reduced pressure to give thetitle compound (6.0 g, 77.9%) as a yellow oil, which was used directlyin the next step without further purification.

MS (ES+) 303.2 [M+Na]⁺, ¹H NMR (500 MHz, CDCl₃) δ 7.85 (dd, J=7.8, 1.8Hz, 1H) 7.50 (ddd, J=8.5, 7.1, 1.8 Hz, 1H) 7.05 (td, J=7.5, 1.0 Hz, 1H)6.97 (d, J=8.4 Hz, 1H) 4.16-4.20 (m, 2H) 4.01 (d, J=4.3 Hz, 2H) 3.90 (s,2H) 2.79 (br. s, 1H) 1.33 (s, 9H).

Preparation 20

Ethyl 3-(2-(2-hydroxyethoxy)phenyl)-3-oxopropanoate

tert-Butyl 3-(2-(2-hydroxyethoxy)phenyl)-3-oxopropanoate (2.0 g, 7.14mmol) in ethanol (20 mL) was heated in a microwave reactor at 120° C.for 90 min. The mixture was cooled to room temperature and the solventwas concentrated under reduced pressure to give a yellow oil. The crudeproduct was purified by flash chromatography (30-40% EtOAc: petroleumether) to give the title compound as a yellow solid.

Preparation 21

(Z)-Ethyl3-((2-amino-2-oxoethyl)amino)-3-(2-(2-hydroxyethoxy)phenyl)acrylate

To a solution of ethyl 3-(2-(2-hydroxyethoxy)phenyl)-3-oxopropanoate (2g, 7.94 mmol) and glycinamide hydrochloride (3.5 g, 31.7 mmol) inmethanol (20 mL) was added triethylamine (3.21 g, 31.7 mmol) at roomtemperature. The mixture was stirred at 40° C. for 20 min. Acetic acid(1.9 g, 31.7 mmol) was added, and the mixture was stirred at 80° C. for18 hours. The reaction mixture was cooled to room temperature andsaturated sodium bicarbonate (200 mL) was added. The organic layer wasseparated, dried (Na₂SO₄) and concentrated to give a yellow solid. Thesolid was washed with EtOAc (20 mL), and the residue was dried underreduced pressure to give the title compound as a white solid. Thismaterial was used without further purification.

Example 349

2-(6-(2-(2-Hydroxyethoxy)phenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide

To a solution of (Z)-ethyl3-((2-amino-2-oxoethyl)amino)-3-(2-(2-hydroxyethoxy)phenyl)acrylate (1.0g, 3.25 mmol) in tetrahydrofuran (15 mL) was added trimethylsilylisothiocyanate (1.7 g, 12.9 mmol), and the mixture was stirred at 80° C.for 18 hours. The reaction mixture was cooled to room temperature,poured into a flask containing water and extracted with CH₂Cl₂ (3×100mL). The combined organic layers were dried and concentrated underreduced pressure to give a yellow solid, which was purified by flashchromatography (2-5% MeOH:CH₂Cl₂) to give the title compound (330 mg,31.7%) as a yellow solid.

MS (ES+) 343.9 [M+Na]. ¹H NMR (DMSO-d6) d: 12.77 (s, 1H), 7.44-7.53 (m,1H), 7.31 (s, 1H), 7.14-7.22 (m, 2H), 7.02 (t, J=7.5 Hz, 1H), 6.98 (br.s., 1H), 5.74-5.82 (m, 1H), 5.34 (br. s., 1H), 4.84 (br. s., 1H),4.00-4.16 (m, 2H), 3.93 (br. s., 1H), 3.65 (q, J=4.4 Hz, 2H)

III. Amide Coupling Route Section Preparation 22

(Z)-Methyl3-(2,4-dimethoxyphenyl)-3-((2-ethoxy-2-oxoethyl)amino)acrylate

To a solution of methyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate (5.0 g,21 mmol) in EtOH (30 mL) was added glycine methyl ester hydrochloride(10.5 g, 83.9 mmol) followed by acetic acid (1.20 mL, 21 mmol) andtriethylamine (8.5 g, 83.9 mmol) and the reaction mixture was heated at100° C. for 18 hours. After cooling to room temperature, the residue waspartitioned between EtOAc and saturated aqueous ammonium chloride. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated in vacuo. The crude product was dissolved in CH₂Cl₂ (10 mL)filtered through a plug of silica gel, eluting with 15-35% EtOAc inheptanes and dried under vacuum to give the title compound (4.7 g, 69%)as a yellow solid. This material was used in the next step withoutfurther purification.

MS (ES+) 324.3 [M+1]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.95 (br. s., 1H) 7.14(d, J=10.57 Hz, 1H) 6.49 (dd, J=8.28, 2.07 Hz, 1H) 6.46 (d, J=2.07, 1H)4.60 (s, 1H) 4.16 (q, J=7.80 Hz, 2H) 3.83 (s, 3H) 3.80 (s, 3H), 3.69 (s,3H), 1.24 (t, J=7.80 Hz, 3H).

Preparation 23

Ethyl2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate

To a solution of (Z)-methyl3-(2,4-dimethoxyphenyl)-3-((2-ethoxy-2-oxoethyl)amino)acrylate (4.68 g,15.1 mmol) in 2-methyltetrahydrofuran (38 mL) was added(trimethylsilyl)isothiocyanate (12.9 mL, 90.8 mmol). The resultingsolution was purged with nitrogen gas for 3 times, and the mixture washeated at 110° C. for 18 hours. The mixture was cooled down to roomtemperature and the solvent was removed under reduced pressure to give ared solid. This residue was suspended in a mixture of 3:1 heptane/EtOAc(200 mL), and it was stirred at room temperature for 1 hour. The solidwas filtered, and triturated with CH₂Cl₂ (100 mL), concentrated underreduced pressure and dried under vacuum the title compound (4.42 g, 87%)as a pink solid. This material was used without further purification inthe next step.

MS (ES+) 351.5 [M+1]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.91 (br s, 1H) 7.13(d, J=6.12 Hz, 1H) 6.54 (s, 1H) 6.51 (d, J=6.12 Hz, 1H) 5.86 (s, 1H)5.44-5.40 (m, 1H) 4.25-4.20 (m, 1H) 4.16-4.06 (m, 2H), 3.86 (s, 3H) 3.83(s, 3H), 1.20 (t, J=6.12 Hz, 3H).

Preparation 24

2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)aceticacid

To a solution of ethyl2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate(6.8 g, 20.3 mmol) in methanol (34 mL) was added 6N aqueous NaOH (16.9mL), and the solution was stirred at 35° C. for 3 hours. The mixture wasconcentrated under reduced pressure, and water (100 mL) was added. Theaqueous layer was washed with ethyl acetate (2×200 mL), and acidifiedwith concentrated HCl to pH ˜2. The resultant acidic aqueous solutionwas extracted with EtOAc (3×200 mL), and the combined organic layerswere dried with sodium sulfate, and concentrated under reduced pressureto give the title compound 6.53 g (99%) as a white solid.

MS (ES+) 323.2 [M+1]⁺. ¹H NMR (500 MHz, CD₃OD) δ 7.16 (d, J=8.86 Hz, 1H)6.67 (s, 1H) 6.64 (d, J=8.86 Hz, 1H) 5.79 (s, 1H) 5.52-5.40 (m, 1H)4.34-4.19 (m, 1H) 3.87 (s, 3H) 3.86 (s, 3H).

Preparation 25

tert-Butyl(2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamido)ethyl)carbamate

To a solution of2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)aceticacid (40 g, 124 mmol) in DMF (300 mL) was added tert-butyl(2-aminoethyl)carbamate (40 g, 250 mmol) and pyridine (30 mL), and themixture was stirred at room temperature for 15 minutes. The solution wascooled to 0° C. and it was purged with nitrogen gas for 3 times. After10 minutes, a 50% solution of T3P in DMF (109 mL) was added drop-wise at0° C., and stirring was continued for 1 hour, whereupon the water/icebath was removed and stirring was continued for 4 hours. The reactionsolution was slowly poured into a stirring solution of aqueous HClsolution (2500 mL, 0.5 M), and the suspension was stirred at roomtemperature for 1 hour. The formed solid was filtered, and the filtercake was washed with 0.5M HCl solution (500 mL) followed by water (500mL). The solid was dried in the vacuum oven at 50° C. for 20 hours togive 54.6 g of light beige powder. This solid was suspended in EtOAc(500 mL), heated to 70° C. under a stream of nitrogen gas with stirringfor 1 hour, and then at room temperature for 18 h. The suspension wascooled down to 0° C., and the solid was filtered, the filter cake washedwith cold (0° C.) EtOAc (100 mL) and dried in the vacuum oven at 50° C.for 9 hours to give 49.0 g of off-white solid. This solid was suspendedin acetonitrile (300 mL), and stirred at 70° C. under a stream ofnitrogen for 18 h. The mixture was cooled to 0° C., and the resultantsolid was filtered, washed with cold acetonitrile (50 mL) and dried inthe vacuum oven at 50° C. for 8 hours to give 46.5 g of off-white solid.This solid was suspended in EtOAc (350 mL), heated to 70° C. under astream of nitrogen gas with stirring for 1 hour, and then at roomtemperature for 18 h. The suspension was cooled down to 0° C., and thesolid was filtered, the filter cake washed with cold (0° C.) EtOAc (50mL) and dried in the vacuum oven at 50° C. for 9 hours to give the titlecompound (45.4 g, 78.8%) as an off-white powder.

MS (ES+) 465.3 [M+1]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.99 (br. s., 1H) 7.16(d, J=7.65 Hz, 1H) 6.65 (s, 1H) 6.62 (d, J=7.65 Hz, 1H) 5.78 (s, 1H)5.51-5.41 (m, 1H) 4.22-4.14 (m, 1H) 3.87 (s, 3H) 3.85 (s, 3H) 3.19-3.11(m, 2H) 3.06-3.00 (m, 2H) 1.42 (s, 9H).

Example 241

N-(2-aminoethyl)-2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamidehydrochloride

To cold (0° C.) ethanol (21.5 mL) under nitrogen was added acetylchloride (1.55 mL) dropwise over 5 minutes, and the reaction mixture wasthen heated at 50° C. for 30 minutes. The reaction mixture was cooled toroom temperature and tert-butyl(2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamido)ethyl)carbamatewas added (1.0 g, 2.15 mmol), followed by heating to 50° C. for 1 hour.The mixture was cooled to room temperature and concentrated underreduced pressure. The residue was suspended in ethanol (10 mL), heatedto 75° C. for 20 minutes, and EtOAc (20 mL) was added and heating wascontinued for another 20 minutes. The mixture was allowed to slowly coolto down to room temperature with stirring during 18 hours. The resultantprecipitate was filtered and dried in a vacuum oven at 70° C. for 20hours to give the title compound (751 mg, 87%) as a white solid.

MS (ES+) 365.2 [M+1]⁺. ¹H NMR (500 MHz, DMSO-D6) δ 12.81 (br. s., 1H)8.26 (br. s., 1H) 8.01 (br. s., 2H) 7.08 (d, J=7.91 Hz, 1H) 6.70 (s, 1H)6.62 (d, J=7.91 Hz, 1H) 5.78 (s, 1H) 5.41-5.35 (m, 1H) 4.07-4.02 (m, 1H)3.84 (s, 3H) 3.83 (s, 3H) 3.20-3.16 (m, 2H) 2.74-2.64 (m, 2H).

IV. Guanidine Route Section Example 350

Methyl[amino({3-[6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]propyl}amino)methylidene]carbamate

To a solution of1-(3-aminopropyl)-6-(5-chloro-2-methoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one(prepared in an analogous manner to Example 6; 50 mg, 0.14 mmol) andmethyl[amino(1H-pyrazol-1-yl)methylidene]carbamate (28 mg, 0.16 mmol) inDMF (0.46 mL) was added N,N-diisopropylethylamine (0.024 mL, 0.14 mmol)at room temperature, and the mixture was stirred for 72 hours. Thesolvent was removed under reduced pressure, the residue was dissolved inDMSO (0.9 mL) and purified using mass-triggered automatic purificationto give the title compound (4.9 mg)

MS (ES+) 425.9 [M+H]⁺. Retention time: 1.54 min; Method: XBridge C18 5um 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min,HOLD at 5% H2O/95% MeCN to 5.0 min. (0.03% NH₄OH). Flow rate: 2 mL/min.

Preparation 26

3,3-Difluoroazetidine-1-carbonitrile

A suspension of 3,3-difluoroazetidine hydrochloride (600 mg, 4.63 mmol)in DCM (15.4 mL) was treated with triethylamine (1.48 mL). The reactionmixture was cooled to 0° C., treated with cyanogen bromide (3M in DCM,2.01 mL, 6.02 mmol) and the reaction mixture was stirred at 0° C. for 2hours. The reaction mixture was diluted with water (10 mL) and saturatedsodium bicarbonate (5 mL), and extracted with ethyl acetate (3×50 mL)and DCM (2×50 mL). The combined organics were dried over sodium sulfate,filtered and concentrated in vacuo. The crude product was dissolved indichlormethane (30 mL) and washed with saturated aqueous ammoniumchloride (2×15 mL). The organic layer was dried over sodium sulfate,filtered and concentrated in vacuo to give the title compound as a lightbrown solid (490 mg, 89%).

¹H NMR (500 MHz, CDCl3) δ 4.52 (t, 4H).

Preparation 27

1-(1H-Benzotriazol-1-yl)-1-(3,3-difluoroazetidin-1-yl)methanimine

A mixture of 3,3-difluoroazetidine-1-carbonitrile (135 mg, 1.14 mmol)and benzotriazole (136 mg, 1.14 mmol) in 1,2-dichloroethane (0.2 mL) washeated to 80° C. under nitrogen for 30 min. A needle was inserted tofacilitate evaporation of the solvent and the mixture was heated at 80°C. for 45 min. The resulting solids were washed with ether (2×3 mL) anddried under reduced pressure to give the title compound as an off-whitesolid (160 mg, 51%).

¹H NMR (500 MHz, DMSO-d₆) δ 8.35 (d, 1H, J=8.4 Hz), 8.15 (d, 1H, J=8.4Hz), 7.92 (s, 1H), 7.67 (t, 1H, J=8.4 Hz), 7.52 (t, 1H, J=8.4 Hz), 4.64(t, 4H, J=12.8 Hz).

Example 351

3,3-Difluoro-N-{3-[6-(5-fluoro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]propyl}azetidine-1-carboximidamide

To a mixture of1-(3-aminopropyl)-6-(5-fluoro-2-methoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one(prepared in an analogous manner to Example 6; 50 mg, 0.14 mmol) and1-(1H-benzotriazol-1-yl)-1-(3,3-difluoroazetidin-1-yl)methanimine (47.5mg, 0.174 mmol) in DMF (0.46 mL) was added N,N-diisopropylethylamine(0.061 mL, 0.35 mmol) under nitrogen and heated at 60° C. under nitrogenfor 1 h. The reaction mixture was cooled to room temperature, andtreated with 4N HCl in dioxane (0.25 mL). The mixture was stirred atroom temperature for 10 min, then concentrated in vacuo and azeotropedwith heptanes (3×10 mL). The residue was dissolved in water (1 mL) andpurified using medium pressure reverse-phase (C18) chromatography (100:0to 70:30 water/acetonitrile) to give the title compound as a white solid(22 mg, 33%).

MS (ES+) 428.2 [M+H]⁺. ¹H NMR (500 MHz, CD3OD) δ 7.36 (ddd, 1H, J=9.1,8.2, 3.2 Hz), 7.21-7.24 (m, 2H), 5.85 (s, 1H), 4.6 (br s, 1H), 4.45 (td,4H, J=11.4, 4.7 Hz), 3.92 (s, 3H), 3.80 (br s, 1H), 3.12 (td, 2H, J=6.0,2.4 Hz), 2.00-2.05 (m, 1H), 1.72-1.82 (m, 1H).

The following Examples of Table 6 (additions to Table 2) were preparedfrom the corresponding carboxylic acid to afford the intermediatebeta-keto-ester as described above for the Preparations in theCarboxylic Acid Route section followed by employing other the methodsdescribed in the I. Beta Keto Ester Route Section as well as standardmethods and techniques known to those skilled in the art.

TABLE 6 Examples from Carboxylic Acid Route Ex- 1H NMR Spectral Data orample Compound Obs HPLC Retention Time and # Structure Name MassConditions 352

N-{2-[6-(2,5- dimethoxyphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin-1(2H)-yl]ethyl} glycinamide 365.2 0.32 min Waters Acqity HSS T3, 2.1 ×50 mm, C18, 1.7 μm; A: 0.1% formic acid in water; Mobile phase B: 0.1%formic acid in MeCN A: 0.1% ammonia in water; Mobile phase B: 0.1%ammonia in MeCN Flow 1.25 ml/min 353

N-{3-[6-(5- chloro-2- methoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)-yl]propyl} methanesulfonamide 404.0 1H NMR (400MHz, CHLOROFORM-d) δ ppm 7.59 (dd, J = 8.8, 2.7 Hz, 1H) 7.54 (d, J = 2.7Hz, 1H) 7.22 (d, J = 9.0 Hz, 1H) 6.86 (t, J = 6.2 Hz, 1H), 5.86 (d, J =2.2 Hz, 1H) 4.28 (br. s., 1H) 3.84 (s, 3H) 3.65 (br. s., 1H) 2.75- 2.78(m, 3H) 2.71 (tt, J = 12.7, 6.3 Hz, 2H) 1.71-1.81 (m, 1H) 1.56-1.66 (m,1H) 354

1-(2-amino ethyl)-6-(1- benzothiophen- 2-yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 305.0 1H NMR (400 MHz, DMSO- d6) δ ppm8.09 (br. s., 1H), 8.01 (br. s., 3H), 7.98 (br. s., 1H), 7.79 (s, 1H),7.49 (br. s., 2H), 6.12 (s, 1H), 4.50 (br. s., 2H), 3.12 (br. s., 2H)355

6-(3,4-dimethoxy- phenyl)-1-(2- hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 309.1 1H NMR (400 MHz, DMSO- d6) δ ppm 7.12(d, J = 1.8 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.01 (dd, J = 8.1, 1.9Hz, 1H), 5.74 (s, 1H), 4.72 (t, J = 5.7 Hz, 1H), 4.19 (t, J = 6.4 Hz,2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.57 (q, J = 6.1 Hz, 2H) 356

6-(2,3-dihydro-1,4- benzodioxin-6-yl)- 1-(2-hydroxyethyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 307.1 1H NMR (400 MHz, DMSO- d6) δ ppm 7.02(d, J = 1.8 Hz, 1H), 6.94-6.97 (m, 1H), 6.92 (dd, J = 8.3, 1.8 Hz, 1H),5.70 (s, 1H), 4.72 (t, J = 5.7 Hz, 1H), 4.25-4.33 (m, 4H), 4.17 (t, J =6.4 Hz, 2H), 3.55 (q, J = 6.1 Hz, 2H) 357

1-(2-aminoethyl)- 6-(2,3-dihydro-1,4- benzodioxin-6-yl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 306.0 1H NMR (400 MHz, DMSO- d6) δ ppm7.89-8.01 (m, 3H), 7.07 (d, J = 1.8 Hz, 1H), 6.92- 7.02 (m, 2H), 5.75(s, 1H), 4.34 (br. s., 2H), 4.30 (br. s., 4H), 2.91-2.98 (m, 2H) 358

2-[6-(2,3-dihydro-1,4- benzodioxin- 6-yl)-4-oxo- 2-thioxo-3,4-dihydropyrimidin- 1(2H)- yl]acetamide 320.0 2.039 min Symmetry-C18 2.1 ×50 mm 3.5 μm Mobile phase-A = 0.1% FA in MeCN, B = 0.1% FA IN water;Time(min)/% B = 0/90, 0.5/90, 2/55, 3/55, 3.5/10, 6.5/10, 7/90; Flow:0.5 mL/min, Column Temp = 40° C.; Diluent: ACN 359

6-(5-chloro- 2-methoxyphenyl)-1- [(2S)-2,3- dihydroxypropyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 343.0 2.018 min AQUITY BEH C-18, 2.1 × 50 mm, 1.7 μm Mobile Phase: A-0.1% FA IN MeCN, B-0.1% FA INwater T/% B(min): 0/90, 0.7/90, 2/55, 3/55, 3.8/5, 5.8/5, 6/90 Flow: 0.5mL/min, Diluent: ACN, Temp - 40° C. 360

1-(2-aminoethyl)- 6-(3,4-dimethoxy- phenyl)-2- thioxo-2,3-dihydropyrimidin- 4(1H)-one 308.1 1H NMR (600 MHz, DMSO- d6) δ ppm 8.44(br. s., 4H), 7.17 (d, J = 1.3 Hz, 1H), 7.09- 7.05 (m, 1H), 7.05-6.96(m, 1H), 5.78 (s, 1H), 4.36 (br. s., 2H), 3.81 (s, 3H), 3.79 (s, 3H),2.97 (t, J = 7.2 Hz, 2H) 361

1-[(2S)-2- aminopropyl]-6- (5-chloro-2- methoxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 326.1 4.82 min XBridge C-18 4.6 × 150 mm,3.5 um M phase: A = MeCN; B = 5 mM ammonium acetate in water; TIME (min)% OF B: 0/95, 1/95, 3/5, 10/5, 10.05/95 flow: 0.8 ml/min, Diluent: ACN362

1-(2-aminoethyl)- 6-(1,3-benzothiazol- 7-yl)-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 305.1 1H NMR (DMSO-d6) δ ppm 9.53 (s, 1H),8.28 (dd, J = 7.5, 1.3 Hz, 1H), 7.80-8.10 (m, 3H), 7.68-7.77 (m, 2H),6.07 (s, 1H), 4.44-4.54 (m, 1H), 4.02 (br. s., 1H), 2.92-2.98 (m, 1H),2.83-2.91 (m, 1H) 363

2-[6-(2,3- dihydro-1,4-benzodioxin- 5-yl)-4-oxo- 2-thioxo-3,4-dihydropyrimidin- 1(2H)-yl] acetamide 319.8 1H NMR (400 MHz, DMSO- d6) δppm 12.84 (br. s., 1H), 7.32 (s, 1H), 7.02 (dd, J = 8.5, 1.5 Hz, 2H),6.91 (t, J = 7.8 Hz, 1H), 6.70-6.76 (m, J = 1.5 Hz, 1H), 5.83 (s, 1H),5.42 (br. s, 1H), 4.26-4.38 (m, 4H), 3.93-4.07 (m, J = 7.0 Hz, 1H) 364

2-[6-(2,3- dihydro-1- benzofuran- 7-yl)-4-oxo- 2-thioxo-3,4-dihydropyrimidin- 1(2H)-yl]acetamide 304.1 1H NMR (400 MHz, DMSO- d6) δppm 12.80 (br. s., 1H), 7.38 (d, J = 7.5 Hz, 2H), 7.00 (d, J = 8.5 Hz,2H), 6.87-6.95 (m, 1H), 5.81 (s, 1H), 5.38- 5.53 (m, 1H), 4.61 (t, J =8.8 Hz, 2H), 3.98-4.11 (m, 1H), 3.24 (t, J = 9.0 Hz, 3H) 365

2-{6-[2-(methyl- sulfanyl)phenyl]- 4-oxo-2-thioxo-3,4- dihydropyrimidin-1(2H) yl}acetamide 307.8 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.48- 7.55(m, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.22-7.32 (m, 2H), 5.81 (s, 1H), 5.54(d, J = 17.1 Hz, 1H), 3.97 (d, J = 18.1 Hz, 1H), 2.54 (s, 3H) 366

1-(2-hydroxy- ethyl)-6-(2- hydroxyphenyl)- 2-thioxo-2,3-dihydropyrimidin- 4(1H)-one 264.7 1H NMR (400 MHz, DMSO- d6) δ ppm 12.71(br. s., 1H), 10.25 (s, 1H), 7.30-7.42 (m, 1H), 7.25 (d, J = 7.5 Hz,1H), 6.86-7.00 (m, 2H), 5.71 (s, 1H), 4.72 (t, J = 5.5 Hz, 1H),4.51-4.63 (m, 1H), 3.60-3.74 (m, 1H), 3.43-3.55 (m, J = 6.0 Hz, 2H) 367

2-[4-oxo-6- (quinolin-5- yl)-2-thioxo-3,4- dihydropyrimidin-1(2H)-yl]acetamide 313.1 1H NMR (400 MHz, DMSO- d6) δ ppm 12.75-13.08 (m, 1H),9.00 (d, J = 2.5 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 8.5 Hz,1H), 7.82-7.91 (m, 1H), 7.62 (br. s., 2H), 7.22 (s, 1H), 6.98 (br. s.,1H), 6.00 (s, 1H) 368

2-[6-(2- hydroxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)-yl]acetamide 277.8 1H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (br. s., 1H),7.37 (br. s., 1H), 7.30-7.36 (m, J = 7.8, 7.8 Hz, 1H), 7.09 (dd, J =7.8, 1.8 Hz, 1H), 6.98 (br. s., 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.84-6.90(m, 1H), 5.76 (s, 1H), 5.43 (br. s., 1H), 3.94 (br. s., 1H), 3.16 (d, J= 5.0 Hz, 1H) 369

N-(2-aminoethyl)- 2-[6-(5- chloro-2- methoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl]acetamide 369.2 1H NMR (400 MHz,DMSO-d6) δ ppm 12.93 (br. s., 1H), 8.24 (br. s., 1H), 7.88 (br. s., 3H),7.57 (d, J = 9.0 Hz, 1H), 7.28-7.10 (m, 2H), 5.93 (s, 1H), 5.43 (d, J =14.1 Hz, 1H), 4.05-3.92 (m, 1H), 3.85 (s, 3H), 3.16 (d, J = 4.5 Hz, 2H),2.76-2.61 (m, 2H) 370

N-(2-aminoethyl)- 2-[6-(2,5- dimethoxyphenyl)- 4-oxo-2-thioxo-3,4-dihydropyrimidin- 1(2H)- yl]acetamide 365.2 1H NMR (400 MHz, DMSO-d6) δppm 12.89 (s, 1H), 8.18 (t, J = 5.5 Hz, 1H), 7.82 (br. s., 3H),7.01-7.16 (m, 2H), 6.75 (s, 1H), 5.86 (d, J = 2.0 Hz, 1H), 5.25-5.53 (m,1H), 4.02 (d, J = 17.1 Hz, 1H), 3.78 (s, 3H), 3.73 (br. s., 3H),3.10-3.20 (m, 2H), 2.59-2.75 (m, 2H) 371

N-(2-amino- ethyl)-2-[6- (5-fluoro-2- methoxyphenyl)-4- oxo-2-thioxo-3,4-dihydro- pyrimidin-1(2H) yl]acetamide 353.1 0.849 min LCMS-C(4#-302)Ultimate XB-C18 2.1 × 30 mm Mobile phase: from 0 MeCN (0.1% TFA) inwater (0.1% TFA) to 60% MeCN (0.1% TFA) in water (0.1% TFA) 372

N-(2-amino- ethyl)-2-[6-(2- methoxyphenyl)-4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]acetamide 335.1 ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 8.28 (t, J = 5.5 Hz, 1H), 7.51-7.59 (m, 1H), 7.27(dd, J = 7.5, 1.5 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 7.01-7.10 (m, 1H),5.84 (s, 1H), 5.45 (d, J = 15.1 Hz, 1H), 4.23 (d, J = 16.1 Hz, 1H), 3.90(s, 3H), 3.35-3.45 (m, 1H), 3.23-3.29 (m, 1H), 2.87- 3.00 (m, 2H) 373

N-(2-aminoethyl)- 2-[6-(2-methoxy-5- methylphenyl)-4- oxo-2-thioxo-3,4-dihydropyrimidin- 1(2H)-yl]acetamide 349.1 1H NMR (400 MHz,METHANOL- d4) δ ppm 7.34 (dd, J = 8.5, 1.5 Hz, 1H), 7.07 (d, J = 2.0 Hz,1H), 7.03 (d, J = 8.5 Hz, 1H), 5.81 (s, 1H), 5.44 (d, J = 14.1 Hz, 1H),4.26 (d, J = 17.1 Hz, 1H), 3.86 (s, 3H), 3.33-3.43 (m, 1H), 3.24- 3.29(m, 1H), 2.85-3.00 (m, 2H), 2.30 (s, 3H) 374

6-(5-fluoro-2- methoxyphenyl)- 1-[3-(methyl- amino)propyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 324.1 1H NMR (400 MHz,methanol- d3): δ ppm 7.33 (td, J = 8.03, 3.01 Hz, 1H), 7.26-7.17 (m,2H), 5.84 (s, 1H), 4.66-4.50 (br s, 1H), 3.89 (s, 3H), 3.85-3.73 (br m,1H), 2.86 (t, J = 7.53 Hz, 2H), 2.62 (s, 3H), 2.15-2.00 (m, 1H),1.96-1.81 (m, 1H) 375

1-{3-[6-(5- fluoro-2- methoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H) yl]propyl}-1- methyl guanidine 366.1 1H NMR (400MHz, DMSO- d6): δ ppm 12.82 (s, 1H), 7.43-7.35 (m, 2H), 7.23-7.17 (m,1H), 7.17-7.06 (br m, 4H), 5.86 (d, J = 2.01 Hz, 1H), 4.45-4.31 (br s,1H), 3.82 (s, 3H), 3.67-3.54 (br m, 1H), 3.19-3.12 (br m, 2H), 2.75-2.65 (m 3H), 1.91-1.73 (m, 1H), 1.72-1.56 (m, 1H) 376

N-carbamimidoyl- 2-[6-(5-chloro- 2-methoxy- phenyl)-4- oxo-2-thioxo-3,4-dihydropyrimidin- 1(2H)-yl] acetamide 367.9 1H NMR (400 MHz,DMSO-d6) δ ppm 13.08 (s, 1H), 11.64 (br s, 1H), 8.19 (br s, 4H), 7.61(dd, J = 9.03, 2.51 Hz, 1H), 7.34-7.30 (m, 1H), 7.22 (d, J = 9.03 Hz,1H), 6.00 (s, 1H), 5.15 (br s, 1H), 4.45 (br s, 1H), 3.83 (s, 3H) 377

2-[6-(5- chloro-2- hydroxyphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin-1(2H)-yl] acetamide 312.0 1H NMR (400 MHz, DMSO-d6) δ ppm 12.80 (br. s.,1H), 10.64 (br. s., 1H), 7.34-7.42 (m, 2H), 7.10 (d, J = 9.5 Hz, 2H),6.95 (d, J = 8.5 Hz, 1H), 5.86 (s, 1H), 5.47 (br. s., 1H), 3.92 (br. s.,1H)

The following Examples of Table 7 (additions to Table 3) were preparedfrom the corresponding methyl ketone to afford the intermediatebeta-keto-ester as described above for the Preparations in the MethylKetone Route section followed by employing other methods described inthe I. Beta Ketone Ester Route Section as well as standard methods andtechniques known to those skilled in the art.

TABLE 7 Examples from Methyl Ketone Route Ex- 1H NMR Spectral Data orample Compound Obs HPLC Retention Time and # Structure Name MassConditions 378

N-(2-amino ethyl)-2-{6-[2- (2-hydroxy ethoxy)-5- methoxyphenyl]-4-oxo-2- thioxo-3,4- dihydropyrimidin- 1(2H)-yl}acetamide 395.1 1.10 minXtimate C18, 2.1 * 30 mm Mobile phase: from 0% MeCN in water (0.1% TFAin water) to 30% MeCN in water (0.1% TFA in water) 379

6-[2-(2- hydroxyethoxy)- 5-methoxy phenyl]-1-(2- hydroxyethyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 339.2 1H NMR (400 MHz,methanol-d4): δ ppm 7.11- 7.04 (m, 2H), 6.94-6.91 (m, 1H), 5.79 (s, 1H),4.74-4.59 (m, 2H), 4.12-4.06 (m, 2H), 3.95-3.83 (m, 1H), 3.83-3.76 (m,6H), 3.68-3.60 (m, 1H) 380

2-{6-[2-(2- hydroxyethoxy)- 5-methoxy phenyl]-4-oxo- 2-thioxo-3,4-dihydropyrimidin- 1(2H)- yl}acetamide 374.1 1H NMR (400 MHz, DMSO- d6) δppm 12.79 (s, 1H), 7.35 (br. s., 1H), 6.99-7.15 (m, 3H), 6.76 (br. s.,1H), 5.81 (s, 1H), 5.24-5.43 (m, 1H), 4.73-4.92 (m, 1H), 4.01 (d, J =5.5 Hz, 2H), 3.84-3.95 (m, 1H), 3.70 (s, 3H), 3.62 (t, J = 5.0 Hz, 2H)381

1-{2-[(2- aminoethyl)amino] ethyl}-6- (2,4-dimethoxy phenyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 351.1 0.77 min Waters Acqity HSST3, 2.1 × 50 mm, C18, 1.7 μm; A: 0.1% formic acid in water; Mobile phaseB: 0.1% formic acid in MeCN A: 0.1% ammonia in water; Mobile phase B:0.1% ammonia in MeCN Flow 1.25 ml/min 382

1-(2-amino- ethyl)-2-thioxo- 6-[2-(trifluoro- methoxy)phenyl]-2,3-dihydropyrimidin- 4(1H)-one 331.9 3.41 min Waters symmetry 2.1 × 50mm 5 μm Mobile phase: from 0% MeCN in water (0.1% TFA) to 30% MeCN inwater (0.1% TFA) 383

6-(2,4-dimethoxy- phenyl)-1-{2-[(2- hydroxyethyl) amino]ethyl}-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 351.9 ¹H NMR (400 MHz, DMSO- d6)δ ppm 8.68 (br. s., 2H), 7.30 (d, J = 8.8 Hz, 1H), 7.10- 7.21 (m, 1H),6.70-6.75 (m, 1H), 6.63-6.69 (m, 1H), 5.76 (s, 1H), 5.18 (br. s., 1H),4.69 (br. s., 1H), 3.99 (br. s., 1H), 3.85-3.81 (m, 6H), 3.70-3.78 (m,1H), 3.55 (t, J = 5.0 Hz, 1H), 3.06 (br. s., 1H), 2.97- 3.01 (m, 1H)2.84 (br. s., 2H) 384

2-[6-(3- methoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin-1(2H)-yl]acetamide 292.0 3.661 min XBRIDGE-C18 4.6 × 75 mm 3.5 μm Mobilephase-A = 0.1% FA IN MeCN, B = 0.1% FA IN water Time(min)/% B = 0/90,0.8/90, 1.8/55, 3/5, 6.5/5, 7/90 Flow: 0.8 mL/min, Column Temp = 40° C.;Diluent: ACN 385

2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]-N-(2- hydroxyethyl)acetamide 365.4 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.98 (br. s., 1H) 7.15 (d, J = 8.5 Hz, 1H) 6.65 (d, J= 2.0 Hz, 1H) 6.60 (dd, J = 8.5, 2.0 Hz, 1H) 5.77 (s, 1H) 5.50 (br. s.,1H) 4.20 (d, J = 15.1 Hz, 1H) 3.87 (s, 3H) 3.85 (s, 3H) 3.41-3.53 (m,2H) 3.14-3.22 (m, 2H) 386

2-[6-(2,6- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]acetamide 321.8 1H NMR (400 MHz, DMSO- d6) δ ppm 12.75 (br.s., 1H) 7.45 (t, J = 8.5 Hz, 1H) 7.13 (br. s., 1H) 6.92 (s, 1H) 6.77 (d,J = 8.0 Hz, 2H) 5.76 (s,1H) 4.33-4.80 (m, 2H) 3.74 (s, 1H) 387

2-{6-[4-(2- hydroxyethoxy)- 2-methoxyphenyl]- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl}acetamide 352.1 ¹H NMR (400 MHz, DMSO- d₆) δppm 12.76 (s, 1H), 7.31 (br. s., 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.98 (s,1H), 6.68 (d, J = 2.0 Hz, 1H), 6.60 (dd, J = 8.5, 2.0 Hz, 1H), 5.74 (d,J = 2.5 Hz, 1H), 5.37 (br. s., 1H), 4.04 (t, J = 5.0 Hz, 2H), 3.89 (br.s., 1H), 3.82 (s, 3H), 3.72 (t, J = 4.8 Hz, 2H) 388

2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]-N- [(3R)-pyrrolidin- 3-yl]acetamide 391.2 0.965 minLCMS-AI(4#-302) Ultimate XB-C18 2.1 × 30 mm Mobile phase: from 0 MeCN(0.1% TFA) in water (0.1% TFA) to 60% MeCN (0.1% TFA) in water (0.1%TFA) 389

1-{2-[(3R)-3- aminopyrrolidin- 1-yl]-2-oxoethyl}- 6-(2,4-dimethoxyphenyl)- 2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 413.2 0.972min LCMS-AI(4#-302) Ultimate XB-C18 2.1 × 30 mm Mobile phase: from 0MeCN (0.1% TFA) in water (0.1% TFA) to 60% MeCN (0.1% TFA) in water(0.1% TFA) 390

N-(2- aminoethyl)-2- [6-(2,4-dimethoxy- phenyl)-4- oxo-2-thioxo-3,4-dihydropyrimidin- 1(2H)- yl]-N-methyl acetamide 379.0 1H NMR (400MHz, METHANOL-d4) δ ppm 7.17 (d, J = 8.5 Hz, 1H), 6.68 (s, 1H), 6.60 (d,J = 7.5 Hz, 1H), 5.80 (s, 1H), 5.65 (d, J = 17.1 Hz, 1H), 4.33 (d, J =16.6 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.59-3.70 (m, 1H), 3.36- 3.49(m, 1H), 3.02 (br. s., 2H), 2.97 (s, 3H) 391

2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]-N- [2-(methylamino) ethyl]acetamide 379.2 ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 8.34 (t, J = 5.8 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H),6.67 (d, J = 2.0 Hz, 1H), 6.62 (dd, J = 8.5, 2.0 Hz, 1H), 5.81 (s, 1H),5.42 (d, J = 16.6 Hz, 1H), 4.28 (d, J = 16.6 Hz, 1H), 3.88 (s, 3H), 3.85(s, 3H), 3.40-3.48 (m, 1H), 3.33-3.38 (m, 1H), 3.00- 3.07 (m, 2H), 2.69(s, 3H) 392

2-[6-(2,4- dimethoxyphenyl)-4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]-N- [2-(dimethylamino) ethyl]acetamide 393.2 ¹H NMR (400 MHz,DMSO- d₆) δ ppm 12.82 (s, 1H), 10.19 (br. s., 1H), 8.28 (br. s., 1H),7.09 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H), 6.62 (dd, J = 8.5,2.0 Hz, 1H), 5.79 (d, J = 2.0 Hz, 1H), 5.37 (d, J = 12.5 Hz, 1H), 4.02(d, J = 16.6 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 2.95 (d, J = 18.1 Hz,2H), 2.70 (br. s., 6H) 393

2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]-N- [(3S)-pyrrolidin- 3-yl]acetamide 391.2 ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 7.16 (dd, J = 8.3, 5.3 Hz, 1H), 6.67 (s, 1H), 6.61(dt, J = 8.5, 2.3 Hz, 1H), 5.79 (s, 1H), 5.39- 5.62 (m, 1H), 4.16-4.34(m, 2H), 3.88 (d, J = 3.5 Hz, 3H), 3.85 (s, 3H), 3.49-3.37 (m, 2H),3.09-3.17 (m, 1H), 2.95- 3.02 (m, 1H), 2.14-2.32 (m, 1H), 1.80-1.98 (m,1H) 394

N-[(2S)-1- aminopropan- 2-yl]-2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl]acetamide 379.2 ¹H NMR (400 MHz,METHANOL-d₄, rotameric mixture) δ ppm 7.20 (d, J = 8.0 Hz, 0.4H) 7.14(d, J = 8.5 Hz, 0.6H) 6.67 (d, J = 2.0 Hz, 1H) 6.61 (td, J = 2.3, 8.5Hz, 1H) 5.81 (s, 0.6H), 5.79 (s, 0.4H) 5.63 (d, J = 15.6 Hz, 1H)5.35-5.27 (m, 1H) 4.35-4.27 (m, 0.4H) 4.20 (d, J = 16.6 Hz, 0.6H)4.05-3.94 (m, 1H) 3.89 (s, 2H), 3.87 (s, 1H) 3.85 (d, J = 1.5 Hz, 3H)3.04-2.92 (m, 0.7H) 2.89-2.77 (m, 1.3H) 1.19 (d, J = 6.5 Hz, 1H) 1.05(d, J = 7.0 Hz, 2H) 395

N-[(2R)-2- aminopropyl]-2- [6-(2,4- dimethoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl]acetamide 379.2 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.22 (t, J = 8.3 Hz, 1H), 6.72 (s, 1H), 6.66 (d, J =8.5 Hz, 1H), 5.86 (s, 1H), 5.37-5.64 (m, 1H), 4.35 (d, J = 15.1 Hz, 1H),3.93 (d, J = 2.5 Hz, 3H), 3.90 (s, 3H), 3.34-3.47 (m, 3H), 1.25 (dd, J =13.3, 5.8 Hz, 3H) 396

N-[(2S)-2- aminopropyl]-2- [6-(2,4- dimethoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl]acetamide 379.2 ¹H NMR (400 MHz,DMSO- d₆) δ ppm 12.81 (br. s., 1H), 8.24 (d, J = 3.0 Hz, 1H), 7.97 (br.s., 3H), 7.07 (dd, J = 11.8, 8.3 Hz, 1H), 6.65-6.73 (m, 1H), 6.59 (ddd,J = 8.4, 4.1, 2.0 Hz, 1H), 5.78 (d, J = 2.0 Hz, 1H), 5.28-5.50 (m, 1H),4.06 (d, J = 15.6 Hz, 1H), 3.83 (d, J = 2.5 Hz, 3H), 3.81 (s, 2H), 3.21(d, J = 6.5 Hz, 1H), 2.93-3.09 (m, 2H), 0.93-1.06 (m, 3H) 397

6-(2,4- dimethoxyphenyl)- 1-[2-oxo-2- (piperazin-1- yl)ethyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 391.2 0.879 min Xtimate C18, 2.1× 30 mm, 3 um Mobile phase: from 0% MeCN in water (0.0685% TFA in water)to 60% MeCN in water (0.0685% TFA in water) 398

1-{2-[(3S)-3- aminopyrrolidin- 1-yl]-2-oxoethyl}-6-(2,4-dimethoxyphenyl)- 2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 413.00.988 min LCMS-AI(4#-302) Xtimate C18, 2.1 × 30 mm, 3 um Mobile phase:from 0% MeCN (0.1% TFA) in water (0.1% TFA) to 60% MeCN (0.1% TFA) inwater (0.1% TFA) 399

N-[2-({[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]acetyl}amino) ethyl]-L- alaninamide 436.0 ¹H NMR (400 MHz,DMSO- d₆) δ ppm 8.33 (s, 1H) 8.12 (br. s., 1H) 8.06 (br. s., 1H) 7.07(d, J = 8.5 Hz, 1H) 6.68 (d, J = 2.5 Hz, 1H) 6.56-6.63 (m, 1H) 5.77 (s,1H), 5.38 (br. s., 1H) 4.22 (br., 3H) 3.97 (d, J = 13.6 Hz, 1H) 3.82-3.88 (m, 3H) 3.81 (s, 3H) 3.37-3.48 (m, 1H) 2.99 (br. s., 4H) 1.17 (d, J= 7.0 Hz, 3H) 400

2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]-N- methyl-N-[2- (methylamino) ethyl]acetamide 393.2 ¹H NMR(METHANOL-d₄, rotameric mixture) δ ppm 7.18 (d, J = 8.5 Hz, 0.6H) 7.13(d, J = 8.5 Hz, 0.4H) 6.67 (d, J = 2.0 Hz, 1H) 6.56-6.63 (m, 1H)5.74-5.81 (m, 1H) 5.66 (d, J = 16.6 Hz, 1H) 4.23-4.38 (m, 1H) 3.87-4.00(m, 3H) 3.80 (s, 3H) 3.53 (dt, J = 13.6, 6.8 Hz, 0.6H) 3.34-3.40 (m,0.4H) 3.14-3.27 (m, 1H) 2.93 (s, 2H) 2.84 (s, 1H) 2.57-2.73 (m, 2H) 2.38(s, 2H) 2.33 (s, 1H) 401

N-[(2R)-1- aminopropan- 2-yl]-2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)-yl]acetamide 379.1 ¹H NMR (400 MHz,METHANOL-d₄, rotameric mixture) δ ppm 7.20 (d, J = 8.0 Hz, 0.4H) 7.14(d, J = 8.5 Hz, 0.6H) 6.67 (d, J = 2.0 Hz, 1H) 6.61 (td, J = 2.3, 8.5Hz, 1H) 5.81 (s, 0.6H) 5.79 (s, 0.4H) 5.63 (d, J = 15.6 Hz, 1H)5.35-5.27 (m, 1H) 4.35-4.27 (m, 0.4H) 4.20 (d, J = 16.6 Hz, 0.6H) 4.05-3.94 (m, 1H) 3.89 (s, 2H) 3.87 (s, 1H) 3.85 (d, J = 1.5 Hz, 3H)3.04-2.92 (m, 0.7H) 2.89-2.77 (m, 1.3H) 1.19 (d, J = 6.5 Hz, 1H) 1.05(d, J = 7.0 Hz, 2H) 402

1-(3- aminopropyl)- 6-[2-(2- hydroxyethoxy)-4- methoxyphenyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 352.2 1H NMR (400 MHz, DMSO-d6) δ ppm 12.75 (s, 1H), 7.73 (br s, 3 H), 7.28 (d, J = 8.03 Hz, 1H),6.72 (d, J = 2.51 Hz, 1H), 6.64 (dd, J = 8.53, 2.51 Hz, 1H), 5.77- 5.73(m, 1H), 4.40 (br s, 1H), 4.10 (t, J = 5.02 Hz, 2H), 3.82 (s, 3H),3.75-3.66 (br s, 1H), 3.64 (t, J = 5.02 Hz, 2H), 2.50-2.51 (m, 2H),1.90-1.78 (m, 1H), 1.78-1.66 (m, 1H) 403

1-(3-{6-[2-(2- hydroxyethoxy)-4- methoxyphenyl]- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl}propyl) guanidine 394.1 1H NMR (400 MHz,DMSO- d6) δ ppm 12.70 (s, 1H), 7.35 (t, J = 6.02 Hz, 1H), 7.25 (d, J =8.53 Hz, 1H), 7.22-6.74 (br s, 4H), 6.71 (d, J = 2.51 Hz, 1H), 6.62 (dd,J = 8.03, 2.51 Hz, 1H), 5.73 (d, J = 2.01 Hz, 1H), 4.87 (br s, 1H), 4.39(br s, 1H), 4.15-4.02 (m, 2H), 3.82 (s, 3H), 3.60-3.74 (m, 3H),2.98-2.93 (m, 2H), 1.85- 1.68 (m, 1H), 1.66-1.51 (m, 1H) 404

N-(2-amino- ethyl)-2-{6-[2-(2- hydroxyethoxy)-4- methoxyphenyl]-4-oxo-2- thioxo-3,4- dihydropyrimidin- 1(2H)- yl}acetamide  395.12 1HNMR (400 MHz, Methanol-d4) δ ppm 8.35- 8.26 (m, 0.3H), 7.18 (d, J = 8.53Hz, 1H), 6.68 (d, J = 2.01 Hz, 1H), 6.62 (dd, J = 8.53, 2.01 Hz, 1H),5.82 (s, 1H), 5.52-5.37 (br m, 1H), 4.42-4.29 (br m, 1H), 4.20- 4.09 (m,2H), 3.90-3.79 (m, 5H), 3.43-3.33 (m, 2H), 3.00- 2.90 (m, 2H) 405

N-(2- aminoethyl)-2- {6-[5-fluoro-2- (2-hydroxyethoxy) phenyl]-4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl}acetamide 383.1 1H NMR (400MHz, Methanol-d4) δ ppm 7.27 (td, J = 9.03, 3.01 Hz, 1H), 7.16 (dd, J =9.03, 4.02 Hz, 1H), 7.08 (dd, J = 8.03, 2.51 Hz, 1H), 5.88 (s, 1H),5.50-5.38 (br m, 1H), 4.36-4.26 (br m, 1H), 4.20-4.10 (m, 2H), 3.84 (t,J = 4.02 Hz, 2H), 3.44-3.33 (m, 2H), 3.00-2.93 (m, 2H) 406

1-(3-aminopropyl)- 6-[5-fluoro-2- (2-hydroxyethoxy) phenyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 340.1 1H NMR (400 MHz,Methanol-d4) δ ppm 7.31 (td, J = 9.03, 3.01 Hz, 1H), 7.25- 7.18 (m, 2H),5.85 (s, 1H), 4.57-4.44 (br s, 1H), 4.03- 3.90 (br m, 2H), 3.97-3.96 (m,1H), 3.84 (t, J = 4.02 Hz, 2H), 2.79 (t, J = 8.03 Hz, 2H), 2.13-2.00 (m,1H), 1.95-1.82 (m, 1H) 407

1-(3-{6-[5- fluoro-2-(2- hydroxyethoxy) phenyl]-4-oxo- 2-thioxo-3,4-dihydropyrimidin- 1(2H)- yl}propyl) guanidine 382.1 1H NMR (400 MHz,Methanol-d4) δ ppm 7.30 (td, J = 9.03, 3.01 Hz, 1H), 7.25- 7.15 (m, 2H),5.84 (s, 1H), 4.60-4.46 (br m, 1H), 4.19- 4.10 (m, 2H), 3.96-3.79 (m,3H), 3.10-3.01 (m, 2H), 2.06- 1.93 (m, 1H), 1.83-1.68 (m, 1H) 408

3-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]propanenitrile 318.1 1H NMR (400 MHz, chloroform-d) δ ppm δ9.57 (br s, 1H), 7.22 (d, J = 8.53 Hz, 1H), 6.62 (dd, J = 8.53, 2.51 Hz,1H), 6.55 (d, J = 2.51 Hz, 1H), 5.85 (d, J = 2.51 Hz, 1H), 4.67-4.53 (brm, 1H), 4.19-4.05 (br m, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.19-3.06 (m,1H), 2.71-2.63 (m, 1H) 409

6-[2-(2- hydroxyethoxy)-4- methoxyphenyl]- 1-(2-hydroxyethyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 338.9 1H NMR (400 MHz, DMSO-d6) δ ppm 12.65 (s, 1H), 7.22 (br s, 1H), 6.78-6.53 (br m, 2H), 5.68 (brs, 1H), 4.90-4.78 (br m, 1H), 4.72- 4.62 (br m, 1H), 4.59-4.42 (br m,1H), 4.19-3.97 (br m, 2H), 3.81 (br s, 3H), 3.64 (br s, 3H) 410

2-[6-(4- methoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin- 1(2H)-yl]acetamide 314.1 0.905 min LCMS-C (4#-302) Ultimate XB-C18 2.1 × 30 mmMobile phase: from 0 MeCN (0.1% TFA) in water (0.1% TFA) to 60% MeCN(0.1% TFA) in water (0.1% TFA) 411

6-[5-fluoro-2- (2-hydroxyethoxy) phenyl]-1-(2- hydroxyethyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 326.8 1H NMR (400 MHz,methanol-d4) δ ppm 7.25 (td, J = 9.03, 3.01 Hz, 1H), 7.19- 7.13 (m, 2H),5.80 (s, 1H), 4.76-4.65 (m, 1H), 4.61 (br s, 1H), 4.16-4.09 (m, 2H),3.88- 3.78 (m, 3H), 3.66-3.60 (m, 1H) 412

2-{6-[5-fluoro- 2-(2-hydroxyethoxy) phenyl]-4-oxo- 2-thioxo-3,4-dihydropyrimidin- 1(2H)- yl}acetamide 362.1 1H NMR (400 MHz,methanol-d4) δ ppm 7.25 (td, J = 9.03, 3.01, 1H), 7.15 (dd, J = 9.03,4.02 Hz, 1H), 7.06 (dd, J = 8.03, 3.01 Hz, 1H), 5.84 (s, 3H), 5.67-5.42(br s, 1H), 4.37-4.18 (br s, 1H), 4.14 (t, J = 4.52 Hz, 2H), 3.83 (t, J= 4.02 Hz, 2H) 413

6-[4-fluoro-2- (2-hydroxyethoxy) phenyl]-1-(2- hydroxyethyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 327.2 1H NMR (400 MHz, DMSO-d6) δ ppm 12.71 (s, 1H), 7.39-7.33 (m, 1H), 7.12 (dd, J = 11.54, 2.01Hz, 1H), 6.90 (td, J = 8.53, 2.51 Hz, 1H), 5.75 (s, 1H), 5.73 (d, J =2.01 Hz, 1H), 4.97-4.79 (br s, 1H), 4.77-4.62 (br s, 1H), 4.53- 4.43 (m,1H), 4.16-4.04 (m, 2H), 3.64 (br t, J = 4.52 Hz, 2H), 3.61-3.49 (m, 2H)414

2-{6-[4-fluoro- 2-(2-hydroxyethoxy) phenyl]-4-oxo- 2-thioxo-3,4-dihydropyrimidin- 1(2H)- yl}acetamide 362.2 1H NMR (400 MHz, DMSO- d6) δppm 12.80 (s, 1H), 7.33 (br s, 1H), 7.24-7.17 (m, 1H), 7.12 (d, J =11.54 Hz, 1H), 7.01 (br s, 1H), 6.91- 6.83 (m, 1H), 5.79 (s, 1H),5.52-5.22 (br s, 1H), 4.97- 4.81 (br m, 1H), 4.17-4.05 (br m, 2H),4.02-3.85 (br s, 1H), 3.69-3.60 (br m, 2H) 415

N-(2-aminoethyl)- 2-{6-[4-fluoro-2- (2-hydroxyethoxy) phenyl]-4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl}acetamide 383.2 1H NMR (400MHz, methanol-d4) δ ppm 8.33- 8.24 (m, 1H), 7.33-7.27 (m, 1H), 7.00 (dd,J = 10.90, 1.71 Hz, 1H), 6.81 (td, J = 8.03, 2.01 Hz, 1H), 5.85 (s, 1H),5.52-5.39 (br m, 1H), 4.37- 4.26 (br m, 1H), 4.23-4.12 (m, 2H), 3.85 (brt, J = 4.02 Hz, 2H), 3.47-3.35 (m, 2H), 3.00-2.91 (m, 2H) 416

2-[6-(2,3- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]acetamide 322.1 1H NMR (400 MHz, DMSO- d6) δ ppm 12.77 (br.s., 1H), 7.26 (br. s., 1H), 7.17-7.23 (m, 1H), 7.08-7.17 (m, 1H), 6.93(br. s., 1H), 6.75 (d, J = 7.5 Hz, 1H), 5.75 (br. s., 1H), 5.42 (br. s.,1H), 4.11 (br. s., 1H), 3.85 (s, 3H), 3.72 (s, 3H) 417

2-[6-(4-chloro- 2-methoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]acetamide 326.2 1H NMR (400 MHz, DMSO- d6) δ ppm 12.81 (br.s., 1H), 7.34 (br. s., 1H), 7.28 (s, 1H), 7.15-7.20 (m, 1H), 7.10-7.14(m, 1H), 7.04 (br. s., 1H), 5.83 (s, 1H), 5.43 (br. s., 1H), 3.86 (s,4H) 418

2-[6-(2- methoxy-4- methylphenyl)- 4-oxo-2-thioxo- 3,4-dihydropyrimidin-1(2H)- yl]acetamide 306.0 1H NMR (400 MHz, DMSO- d6) δ ppm 12.78 (br.s., 1H), 7.04 (d, J = 7.5 Hz, 1H), 7.00 (s, 2H), 6.85 (d, J = 7.5 Hz,1H), 5.75 (s, 1H), 5.35 (br. s., 1H), 3.86-3.94 (m, 1H), 3.82 (s, 3H),2.36 (s, 3H) 419

1-{2-[6-(5- fluoro-2- methoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)-yl] ethoxy}guanidine 354.2 1H NMR (400 MHz,METHANOL-d4) δ ppm 8.45 (br. s., 1H), 7.30 (td, J = 8.5, 3.0 Hz, 1H),7.10-7.24 (m, 2H), 5.83 (s, 1H), 4.73-4.83 (m, 1H), 3.97-4.16 (m, 3H),3.89 (s, 3H) 420

2-{6-[2-(2- hydroxyethoxy)- 4-methoxyphenyl]- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl}acetamide 374.0 1H NMR (400 MHz, DMSO- d6) δppm 12.72 (br. s., 1H), 7.32 (br. s., 1H), 7.09 (d, J = 8.0 Hz, 1H),6.97 (br. s., 1H), 6.69 (br. s., 1H), 6.60 (d, J = 9.0 Hz, 1H), 5.74 (d,J = 11.0 Hz, 1H), 5.32 (br. s., 1H), 4.84 (br. s., 1H), 4.08 (d, J = 4.0Hz, 2H), 3.97 (br. s., 1H), 3.80 (s, 3H), 3.64 (br. s., 2H) 421

2-{2-[3-(2- amino-2- oxoethyl)-6- oxo-2-thioxo- 1,2,3,6-tetrahydropyrimidin- 4-yl]-4- fluorophenoxy} ethyl acetate 404.1 1H NMR(400 MHz, METHANOL-d4) δ ppm 8.09 (s, 0.6H), 7.57 (br. s., 0.2H), 7.27(td, J = 8.5, 3.0 Hz, 1H), 7.14 (dd, J = 9.0, 4.5 Hz, 1H), 7.07 (dd, J =8.3, 3.3 Hz, 1H), 6.99 (br. s., 0.2H), 5.83 (s, 1H), 5.67 (d, J = 14.1Hz, 1H), 4.30-4.46 (m, 2H), 4.22-4.30 (m, 2H), 4.12 (d, J = 17.1 Hz,1H), 2.06 (s, 3H)

The following Examples of Table 8 (additions to Table 4) were preparedfrom the corresponding aryl halide to afford the intermediatebeta-keto-ester as described above for the Preparations in the ArylHalide Route section followed by employing the methods described in theI. Beta Keto Ester Route Section as well as standard methods andtechniques known to those skilled in the art.

TABLE 8 Examples from Aryl Halide Route Ex- 1H NMR Spectral Data orample Compound Obs HPLC Retention Time and # Structure Name MassConditions 422

2-{6-[5-(2- hydroxyethoxy)- 2-methoxy phenyl]-4-oxo- 2-thioxo-3,4-dihydropyrimidin- 1(2H)- yl}acetamide 352.0 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.09- 7.18 (m, 1H), 7.03-7.09 (m, 1H), 6.88 (d, J =3.0 Hz, 1H), 5.81 (s, 1H), 5.46-5.63 (m, 1H), 4.17 (br. s., 1H), 4.00(d, J = 3.5 Hz, 2H), 3.84 (s, 5H) 423

2-{4-[3-(2- aminoethyl)-6- oxo-2-thioxo- 1,2,3,6- tetrahydropyrimidin-4-yl]-3- methoxyphenoxy}- acetamide 351.2 1H NMR (400 MHz, DMSO- d6) δppm 12.85 (s, 1H) 8.06 (br s, 3H) 7.69 (s, 1H) 7.48 (s, 1H) 7.30 (d, J =8.53 Hz, 1H) 6.82 (d, J = 2.01 Hz) 1H) 6.67 (dd, J = 8.53, 2.01 Hz, 1H)5.75 (s, 1H) 4.71-4.60 (br s, 1H) 4.51 (s, 2H) 3.94- 3.81 (m, 4H)2.95-2.80 (m, 2H)

The following Examples of Table 9 were prepared from the correspondingaryl ester or lactone to afford the intermediate beta-keto-ester asdescribed above for the Preparations in the Ester Route section followedby employing the methods described in the I. Beta Keto Ester RouteSection as well as standard methods and techniques known to thoseskilled in the art.

TABLE 9 Examples from Ester Route Ex- 1H NMR Spectral Data or ampleCompound Obs HPLC Retention Time and # Structure Name Mass Conditions424

N-(2- aminoethyl)-2- {6-[5-chloro-2- (2-hydroxy ethoxy)phenyl]-4-oxo-2-thioxo- 3,4-dihydro- pyrimidin- 1(2H)- yl}acetamide 398.9 1H NMR(400 MHz, Methanol-d4) δ ppm 7.50 (dd, J = 9.03, 3.01 Hz, 1H), 7.30 (d,J = 2.51 Hz, 1H), 7.17 (d, J = 9.03 Hz, 1H), 5.88 (s, 1H), 5.56-5.43 (brm, 1H), 4.31-4.06 (m, 4H), 3.84 (t, J = 4.52 Hz, 2H), 3.44-3.33 (m, 2H),3.03-2.89 (m, 2H) 425

6-[5-chloro-2- (2-hydroxyethoxy) phenyl]-1-(2- hydroxyethyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 342.7 1H NMR (400 MHz, DMSO-d6) δ ppm 12.73 (br s, 1H), 7.52 (br s, 1H), 7 40 (br s, 1H), 7.28-7.15(br m, 1H), 5.88-5.72 (br m, 1H), 4.92 (br s, 1H), 4.78 (br s, 1H), 4.48(br s, 1H), 4.08 (br s, 2H), 3.73-3.52 (br m, 4H) 426

2-{6-[5-chloro- 2-(2- hydroxyethoxy) phenyl]-4-oxo- 2-thioxo-3,4-dihydropyrimidin- 1(2H)- yl}acetamide 378.1 1H NMR (400 MHz, DMSO- d6) δppm 12.84 (br. s, 1H), 7.54 (dd, J = 9.0, 3.0 Hz, 1H), 7.35 (s, 1H),7.21 (d, J = 8.5 Hz, 2H), 7.09 (s, 1H), 5.87 (s, 1H), 5.37 (br. s., 1H),4.86 (t, J = 5.3 Hz, 1H), 4.04-4.13 (m, 2H), 3.95 (br. s., 1H),3.58-3.70 (m, 2H) 427

1-(2- aminoethyl)-6- [5-chloro-2-(2- hydroxyethoxy) phenyl]-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 341.9 1H NMR (400 MHz,METHANOL-d4) δ ppm 8.49 (br. s., 1H) 7.56 (dd, J = 9.3, 2.3 Hz, 1H) 7.45(d, J = 2.5 Hz, 1H) 7.22 (d, J = 9.0 Hz, 1H) 5.87 (s, 1H) 4.62 (br. s.,2H) 4.12-4.30 (m, 3H) 3.85 (br. s., 2H) 3.14-3.25 (m, 1H) 3.04-3.13 (m,J = 8.0 Hz, 1H) 428

N-(2- aminoethyl)-2- {6-[2-(2- hydroxyethoxy) phenyl]-4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl}acetamide 365.1 ¹H NMR (400MHz, METHANOL-d₄) δ ppm 8.28 (t, J = 5.8 Hz, 1H) 7.48-7.55 (m, 1H) 7.27(dd, J = 7.5, 1.5 Hz, 1H) 7.16 (d, J = 8.0 Hz, 1H) 7.06 (td, J = 7.5,1.0 Hz, 1H) 5.85 (s, 1H), 5.44 (br. s., 1H) 4.31 (d, J = 15.1 Hz, 1H)4.13-4.20 (m, 2H) 3.85 (ddd, J = 5.4, 3.9, 2.3 Hz, 2H) 3.33- 3.40 (m,2H) 2.92 (t, J = 5.8 Hz, 2H)

The following Examples of Table 10 were prepared from the correspondingthiouracil carboxylic acid as described above for the Preparations inthe Ill. Amide Coupling Route section and by employing the methodsdescribed in the I. Beta Keto Ester Route Section as well as standardmethods and techniques known to those skilled in the art.

TABLE 10 Examples from Amide Coupling Route Ex- 1H NMR Spectral Data orample Compound Obs HPLC Retention Time and # Structure Name MassConditions 429

N-(2-amino-2- methylpropyl)- 2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl]acetamide 392.2 ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 8.42 (t, J = 6.3 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H),6.68 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 5.82 (s, 1H), 5.41(d, J = 13.6 Hz, 1H), 4.31 (d, J = 15.6 Hz, 1H), 3.88 (s, 3H), 3.85 (s,3H), 3.34-3.40 (m, 1H), 3.09-3.17 (m, 1H), 1.22- 1.29 (m, 5H), 1.26 (d,J = 5.5 Hz, 6H) 430

N-(cis-3- aminocyclobutyl)- 2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl]acetamide 391.2 ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 8.31 (d, J = 6.5 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H),6.67 (d, J = 2.0 Hz, 1H), 6.60 (dd, J = 8.3, 2.3 Hz, 1H), 5.79 (s, 1H),5.53 (br. s., 1H), 4.20 (br. s., 1H), 3.90-3.98 (m, 1H), 3.88 (s, 3H),3.86 (s, 3H), 3.43-3.52 (m, 1H), 2.57-2.76 (m, 2H), 1.93-2.14 (m, 2H)431

1-[2-(3- aminoazetidin- 1-yl)-2- oxoethyl]-6- (2,4-dimethoxy phenyl)-2-thioxo-2,3- dihydropyrimidin- 4(1H)-one 377.1 1H NMR (400 MHz,METHANOL-d₄) δ ppm 7.21 (dd, J = 14.05, 8.53 Hz, 1H), 6.70-6.58 (m, 2H),5.80 (s, 1H), 5.38-5.28 (br m, 1H), 5.18-5.09 (br m, 1H), 4.44- 4.25 (m,5H), 4.23-4.11 (m, 2H), 4.11-3.92 (m, 1H), 3.86 (s, 6H) 432

N-(1-amino-2- methylpropan- 2-yl)-2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl]acetamide 392.9 1H NMR (400 MHz,DMSO- d6) δ ppm 12.81 (br s, 1H), 7.81 (s, 1H), 7.79-7.63 (br s, 3H),7.08 (d, J = 8.03 Hz, 1H), 6.70 (s, 1H), 6.61 (d, J = 8.50 Hz, 1H), 5.77(s, 1H), 5.42 (br s, 1H), 4.05 (br s, 1H), 3.83 (s, 3H), 3.81 (s, 3H),2.94 (s, 2H), 1.13 (s, 3H), 1.09 (s, 3H) 433

N-[(2R,3R)-3- aminobutan-2- yl]-2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl]acetamide 393.1 0.931 minXtimate C18 2.1 × 30 mm 3 um Mobile phase: from 0% MeCN (0.1% TFA) inwater (0.1% TFA) to 60% MeCN (0.1% TFA) in water (0.1% TFA) 434

2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]-N- ethylacetamide 349.9 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.75 (br, 1H), 7.20 (d, J = 8.53 Hz, 1H), 6.55 (dd, J = 8.53, 2.51 Hz,1H), 6.49 (d, J = 2.51 Hz, 1H), 5.87 (s, 1H), 5.62 (br, 1H), 5.12 (br,1H), 4.25 (br, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.36-3.24 (m, 1H),3.24-3.14 (m, 1H), 1.10 (t, J = 7.53 Hz, 3H) 435

2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]-N- propylacetamide 364.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.61 (br, 1H), 7.21 (d, J = 8.53 Hz, 1H), 6.54 (dd, J = 8.53, 2.51 Hz,1H), 6.49 (d, J = 2.51 Hz, 1H), 5.87 (s, 1H), 5.64 (br, 1H), 5.15 (br,1H), 4.26 (br, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.30-3.18 (m, 1H),3.15-3.04 (m, 1H), 1.48 (q, J = 7.03, 2H), 0.88 (t, J = 7.03 Hz, 3H) 436

2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]-N- (2-methoxyethyl) acetamide 402.1 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 9.59 (br, 1H), 7.22 (d, J = 8.53 Hz, 1H), 6.54 (dd,J = 8.53, 2.51, 1H), 6.49 (d, J = 2.51 Hz, 1H), 5.99 (br s, 1H), 5.86(s, 1H), 5.18 (br s, 1H), 4.22 (br s, 1H), 3.85 (s, 3H), 3.82 (s, 3H)3.51-3.38 (m, 3H), 3.36-3.28 (m, 4H) 437

N-(trans-3- aminocyclobutyl)- 2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl]acetamide 391.2 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.13 (d, J = 8.53 Hz, 1H), 6.67 (d, J = 2.01 Hz, 1H),6.59 (dd, J = 8.53, 2.01 Hz, 1H), 5.78 (s, 1H), 5.68-5.43 (br s, 1H),4.38-4.27 (m, 1H), 4.27-4.13 (br m, 1H), 3.88 (s, 3H), 3.85 (s, 3H),3.83-3.73 (m, 1H), 2.50-2.33 (m, 3H), 2.32-2.22 (m, 1H). 438

N-(azetidin-3- yl)-2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]acetamide 377.1 1H NMR (400 MHz,METHANOL-d4) δ ppm 8.71 (d, J = 6.02 Hz, 1H), 7.15 (d, J = 8.53 Hz, 1H),6.69-6.65 (m, 1H), 6.60 (dd, J = 8.53, 2.01 Hz, 1H), 5.80 (s, 1H), 5.54(br s, 1H), 4.59-4.48 (m, 1H), 4.27-4.15 (m, 3H), 4.13- 3.98 (m, 2H),3.88 (s, 3H), 3.85 (s, 3H). 439

N-[(1S,2S)-2- aminocyclobutyl]- 2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl]acetamide 391.1 0.903 minXtimate C18 2.1 × 30 mm 3 um Mobile phase: from 0% MeCN in water(0.0685% TFA in water) to 60% MeCN in water (0.0685% TFA in water) 440

N-{2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)- yl]ethyl}-N- methylglycinamide 378.9 1H NMR (400 MHz, DMSO- d6) δppm 12.90 (s, 0.33H), 12.75 (s, 0.66H), 8.02 (br s, 3H), 7.33 (d, J =8.53 Hz, 0.33H), 7.30 (d, J = 8.53 Hz, 0.66H), 6.72-6.66 (m, 2H), 5.83(s, 0.33H), 5.73 (s, 0.66H), 4.66-4.44 (br m, 1H), 3.86-3.81 (m, 6H),3.79-3.64 (m, 3H), 3.62-3.51 (m, 1H), 2.62 (s, 2H), 2.40 (s, 1H) 441

N-[(1R,2R)-2- aminocyclobutyl]- 2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl]acetamide 391.2 0.897 minXtimate C18, 2.1 × 30 mm 3 um Mobile phase: from 0% MeCN (0.1% TFA) inwater (0.1% TFA) to 60% MeCN (0.1% TFA) in water (0.1% TFA) 442

N-(3- aminopropyl)- 2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]acetamide 379.1 1H NMR (400 MHz,METHANOL-d4) δ ppm 8.25 (t, 0.5H), 7.17 (d, J = 8.53 Hz, 1H), 6.66 (d, J= 2.01 Hz, 1H), 6.61 (dd, J = 8.53, 2.01 Hz, 1H), 5.80 (s, 1H), 5.36 (brs, 1H), 4.19-4.35 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.21- 3.05 (m,2H), 2.98-2.90 (m, 2H), 1.85-1.75 (m, 2H). 443

N-(3-amino-2,2- difluoropropyl)- 2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2-thioxo-3,4- dihydropyrimidin- 1(2H)- yl]acetamide 437.1 0.888 minXtimate C18 2.1 × 30 mm 3 um Mobile phase: from 0% MeCN in water (0.1%TFA in water) to 60% MeCN in water (0.1% TFA in water) 444

N-(2- aminoethyl)-3- [6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]propanamide 379.1 1H NMR (400 MHz,METHANOL-d4) δ ppm 7.23 (d, J = 8.53 Hz, 1H), 6.68 (d, J = 2.01 Hz, 1H),6.65 (dd, J = 8.53, 2.01 Hz, 1H), 5.75 (s, 1H), 4.81-4.70 (br s, 1H),4.07-3.95 (br m, 1H), 3.88 (s, 3H), 3.87 (s, 1H), 3.93-3.32 (m, 2H),3.01-2.95 (m, 2H), 2.70-2.48 (m, 2H), 1.40-1.35 (m, 2H). 445

N-{2- [(cyclopropyl- methyl)amino] ethyl}-2-[6-(2,4- dimethoxyphenyl)-4-oxo-2- thioxo-3,4- dihydropyrimidin- 1(2H)- yl]acetamide 419.1 1H NMR(400 MHz, METHANOL-d4) δ ppm 8.42- 8.35 (m, 1H), 7.52-7.45 (m, 0.5H),7.30-7.33 (m, 0.5H), 7.18 (d, J = 8.53 Hz, 1H), 6.69-6.66 (m, 1H),6.64-6.60 (m, 1H), 5.82 (s, 1H), 5.49 (s, 1H), 5.44-5.28 (br s, 1H),4.35-4.22 (br m, 1H), 3.88 (s, 3H), 3.85 (s, 1H), 3.54-3.42 (m, 1H),3.15-2.99 (m, 2H), 2.95-2.86 (m, 2H), 1.12-1.01 (m, 1H), 0.73-0.66 (m,2H), 0.43-0.37 (m, 2H). 446

N- carbamimidoyl- 3-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]propanamide 377.9 1H NMR (400 MHz, DMSO- d6)δ ppm 12.81 (s, 1H), 11.82 (br s, 1H) 8.51-7.95 (br m, 4H) 7.27 (d, J =8.53 Hz, 1H) 6.69 (d, J = 2.01 Hz, 1H) 6.63 (dd, J = 8.53, 2.01 Hz, 1H)5.76 (d, J = 2.01 Hz, 1H) 4.57-4.41 (br m, 1H) 4.03- 3.90 (br m, 1H)3.86-3.78 (m, 6H) 2.82-2.71 (m, 2H).

The following Examples of Table 11 were prepared from the correspondingthiouracil amines as described above for the Preparations in the IV.Guanidine Route section and by employing the methods described in the I.Beta Keto Ester Route Section as well as standard methods and techniquesknown to those skilled in the art.

TABLE 11 Examples from Guanidine Route Ex- 1H NMR Spectral Data or ampleCompound Obs HPLC Retention Time and # Structure Name Mass Conditions447

1-cyano-3-{3- [6-(5-fluoro-2- methoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]propyl} guanidine 377.2 1H NMR (400 MHz,DMSO- d6) δ ppm 12.78 (s, 1H), 7.41-7.34 (m, 2H), 7.16 (dd, J = 9.03,4.02 Hz, 1H), 6.94- 6.31 (br s, 3H), 5.85 (s, 1H), 4.26 (br s, 1H), 3.82(s, 3H), 3.72-3.58 (br m, 1H), 2.91- 2.75 (m, 2H), 1.77-1.66 (br m, 1H),1.61-1.46 (br m, 1H). 448

1-(2-{6-[5- chloro-2-(2- hydroxyethoxy) phenyl]-4-oxo- 2-thioxo-3,4-dihydropyrimidin- 1(2H)-yl}ethyl) guanidine 383.9 1.31 min Atlantis dC185 um 4.6 × 50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05% formic acid). Flow rate:2 mL/min. 449

1-{3-[6-(5- chloro-2-methoxy- phenyl)-4- oxo-2-thioxo-3,4-dihydropyrimidin- 1(2H)- yl]propyl}-2- ethylguanidine 395.9 1.62 minAtlantis dC18 5 um 4.6 × 50 mm, 95% H2O/5% MeCN linear to 5% H2O/95%MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05%trifluoroacetic acid). Flow rate: 2 mL/min. 450

N-{3-[6-(5- chloro-2-methoxy- phenyl)-4- oxo-2-thioxo- 3,4-dihydro-pyrimidin-1(2H)- yl]propyl} pyrrolidine-1- carboximidamide 422.0 2.02min Atlantis dC18 5 um 4.6 × 50 mm, 95% H2O/5% MeCN linear to 5% H2O/95%MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05%trifluoroacetic acid). Flow rate: 2 mL/min. 451

1-{3-[6-(5- chloro-2-methoxy- phenyl)-4- oxo-2-thioxo- 3,4-dihydro-pyrimidin-1(2H)- yl]propyl}-3- (2,2-difluoro propyl) guanidine 446.2 1HNMR (500 MHz, METHANOL-d4) δ ppm 7.58 (m, 2H), 7.43 (m, 2H), 7.31 (br s,1H), 7.20 (d, J = 8.8 Hz, 1H), 5.84 (s, 2H), 4.56 (br s, 1H), 3.92 (s,3H), 3.81 (br s, 1H), 3.62 (td, J = 14.0, 6.4 Hz, 2H), 3.15 (q, J = 6.8Hz, 2H), 1.95-2.03 (m, 1H), 1.75-1.85 (m, 1H), 1.67 (t, J = 18.2 Hz,3H). 452

1-carbamimidoyl- 3-{2-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4-dihydropyrimidin- 1(2H)- yl]ethyl}urea 393.1 1.002 min Xtimate C18 2.1 ×30 mm, 3 um Mobile phase: from 0% MeCN (0.1% TFA) in water (0.1% TFA) to60% MeCN (0.1% TFA) in water (0.1% TFA) 453

2-{3-[6-(2,4- dimethoxyphenyl)- 4-oxo-2- thioxo-3,4- dihydropyrimidin-1(2H)-yl]-2,2- difluoropropyl} guanidine 400.1 1H NMR (400 MHz, DMSO-d6) δ ppm 12.96 (s, 1H), 7.81-7.72 (m, 1H), 7.59-7.24 (br s, 4H),7.23-7.16 (m, 2H), 6.70-6.67 (m, 1H), 6.64 (dd, J = 8.53, 2.01 Hz, 1H),5.82 (d, J = 1.51 Hz, 1H), 5.79-5.61 (m, 1H), 3.89-3.80 (m, 6H),3.75-3.62 (m, 2H)

All publications, including but not limited to, issued patents, patentapplications, and journal articles, cited in this application are eachherein incorporated by reference in their entirety.

Although the invention has been described above with reference to thedisclosed embodiments, those skilled in the art will readily appreciatethat the specific experiments detailed are only illustrative of theinvention. It should be understood that various modifications can bemade without departing from the spirit of the invention.

What is claimed:
 1. The compound2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamideor a pharmaceutically acceptable salt thereof.
 2. The compound havingthe Formula


3. A method of treating cardiovascular conditions comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt of said compound wherein the cardiovascular condition isstroke, primary or secondary myocardial infarction, heart failure,congestive heart failure, peripheral arterial disease, pulmonaryhypertension, vasculitis or unstable angina or the mammal hasexperienced myocardial infarction.
 4. A pharmaceutical composition whichcomprises a therapeutically effective amount of a compound of claim 1 ora pharmaceutically acceptable salt of said compound and apharmaceutically acceptable carrier, vehicle or diluent.
 5. Apharmaceutical combination composition comprising: a therapeuticallyeffective amount of a composition comprising: a first compound, saidfirst compound being a compound of claim 1, or a pharmaceuticallyacceptable salt of said compound; a second compound, said secondcompound being an angiotensin converting enzyme inhibitor, a HMG-CoAreductase inhibitor, a non-steroidal anti-inflammatory agent, a FactorXa inhibitor or warfarin; and a pharmaceutical carrier, vehicle ordiluents.